Devices, formulations, and methods for delivery of multiple beneficial agents

ABSTRACT

The present invention relates to osmotic delivery devices, formulations, and methods for delivery of two or more beneficial agents. In one aspect, the present invention provides osmotic delivery devices useful for substantially concurrent administration of two or more beneficial agents. In another aspect, the present invention provides beneficial agent formulations for use in the osmotic delivery devices. The formulations include formulations wherein beneficial agents are soluble in the vehicle, suspension formulations comprising particle formulations of one or more beneficial agent, and combinations thereof. Further, methods for treatment of a variety of diseases or conditions using two or more beneficial agents are disclosed, wherein the methods are preferably practiced using the osmotic delivery devices and/or formulations of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. patent application Ser. No.13/689,410, filed Nov. 29, 2012. U.S. Ser. No. 13/689,410 claims thebenefit of U.S. patent application Ser. No. 12/378,341, filed Feb. 12,2009, now U.S. Pat. No. 8,343,140. U.S. Ser. No. 12/378,341 claims thebenefit of U.S. Provisional Patent Application No. 61/065,692, filedFeb. 13, 2008. The contents of the above-listed patent applications areherein incorporated by reference in their entirety.

TECHNICAL FIELD

The present invention relates to devices, formulations, and methods foradministration of two or more beneficial agents, for example, for thetreatment of one or more disease or condition, wherein the two or morebeneficial agents are administered to a subject over a period of time,for example, about two weeks, about four weeks, about six weeks, abouteight weeks, about three months, about six months, or up to about ayear.

BACKGROUND

Several approaches have been taken for prolonged delivery of a drug at acontrolled rate. For example, the NORPLANT™ (The Population Council NewYork, N.Y.) device uses implantable diffusional systems. The NORPLANT™device required the placement of 6 levonorgestrel-filled silasticcapsules under the skin (Darney, Current Opinion in Obstetrics andGynecology 3:470-476 (1991)). Protection from conception for up to fiveyears was achieved. The implants operated by simple diffusion, that is,the drug diffused through a polymeric material at a rate that wascontrolled by the characteristics of the drug formulation and thepolymeric material. Darney describes other biodegradable implants, e.g.,the CAPRANOR™ (University of California, San Francisco, Calif.) systemand norethindrone pellets. These systems were designed to delivercontraceptives for about one year and then dissolve. The CAPRANOR™system used poly(ε-caprolactone) capsules filled with levonorgestrel.Norethindrone pellets typically consisted of 10% pure cholesterol with90% norethindrone.

Implantable infusion pumps have also been described for delivering drugsby intravenous, intraarterial, intrathecal, intraperitoneal, andepidural pathways. Such pumps are typically surgically insertedsubcutaneously into a pocket of tissue in the lower abdomen provide forcontrolled delivery of an drug. A number of systems for insulindelivery, pain management, and chemotherapy delivery have been described(e.g., Health Services/Technology Assessment Text (HSTAT), External andImplantable Infusion Pumps, by Ann A. Graham, C.R.N.A., M.P.H., ThomasV. Holohan, M.D., Health Technology Review, No. 7, Agency for HealthCare Policy and Research Office of Health Technology Assessment, January1994).

Another approach for prolonged delivery of a drug uses osmotic deliverydevices. Such a device can be implanted into a subject to release a drugin a controlled manner for a predetermined administration period. Ingeneral, these devices operate by imbibing fluid from the outsideenvironment and releasing amounts of the drug corresponding to theimbibed fluid. An example of one such osmotic delivery device is theVIADUR™ (Bayer HealthCare Pharmaceuticals, Wayne, N.J.) device. TheVIADUR™ device is a titanium implant drug-delivery system using DUROS™(ALZA Corporation, Mountain View, Calif.) technology to manage thesymptoms associated with advanced (stage 4) prostate cancer bydelivering leuprolide acetate. Treatment using the VIADUR™ devicereduces the amount of testosterone produced and circulated in asubject's body and provides a continuous therapy for 12 months.

The above-described devices and formulations have been useful fordelivering drugs to a fluid environment of use. Although these deviceshave found application for human and veterinary purposes, there remainsa need for devices, formulations, and methods of administration that arecapable of delivering multiple drugs reliably to a subject at acontrolled rate over a prolonged period of time.

SUMMARY

In one aspect, the present invention relates to osmotic delivery devicescomprising multiple beneficial agent chambers. Several embodiments aredescribed for dual osmotic delivery devices as well as embodiments ofmultiple osmotic delivery device, comprising at least two and preferablythree or more beneficial agent chambers. Components and examples ofmaterials, from which the components can be made for use in, manufactureof, and assembly of the osmotic delivery devices, are described.Further, components and formulations are provided for osmotic agentformulations and beneficial agent formulations.

In another aspect the present invention relates to combined formulationsof beneficial agents. In one embodiment, this aspect of the presentinvention relates to an osmotic delivery device comprising a beneficialagent chamber containing two or more beneficial agents. The beneficialagent chamber typically contains a beneficial agent formulationcomprising two or more beneficial agents and a viscous vehicle. Examplesof such beneficial agent formulations include, but are not limited to,the following: (i) two or more beneficial agents dispersed directly inthe vehicle; (ii) one or more beneficial agents dispersed directly inthe vehicle and one or more beneficial agent formulated into one or moreparticle formulation that is suspended in the vehicle; (iii) two or morebeneficial agents combined in one particle formulation and the particleformulation suspended in the vehicle; and (iv) two or more beneficialagents formulated individually into different particle formulations andthe different particle formulations suspended together in the vehicle.The two or more beneficial agents may be, but are not limited to, smallmolecules, peptides, polypeptides, proteins, polynucleotides (e.g., RNAimolecules), and combinations thereof. Examples of beneficial agents areprovided herein.

In another aspect of the present invention relates to osmotic deliverydevices loaded with beneficial agent formulations.

In another aspect, the present invention relates to a method of treatinga disease or condition in a subject in need of treatment, comprisingproviding a dual or multiple osmotic delivery device of the presentinvention to the subject, wherein the osmotic delivery device delivers atherapeutically effective amount of two or more beneficial agents totreat the disease or condition. The dual or multiple osmotic deliverydevice is implanted in the subject. One or more such dual or multipleosmotic delivery device may be implanted.

In another embodiment, the present invention relates to a method oftreating two or more diseases or conditions in a subject in need oftreatment, comprising providing a dual or multiple osmotic deliverydevice of the present invention to the subject, wherein the osmoticdelivery device delivers a therapeutically effective amount of (i) oneor more beneficial agent to treat a first disease or condition, and (ii)one or more beneficial agent to treat a second disease or condition. Thedual or multiple osmotic delivery device is implanted in the subject.One or more such dual or multiple osmotic delivery device may beimplanted.

In another aspect the present invention provides a method of treatingone or more disease or condition in a subject in need of treatment. Inthis method, a first osmotic delivery device is provide comprising afirst beneficial agent chamber that contains a first beneficial agentformulation, and a second osmotic delivery device is provided comprisinga second beneficial agent chamber that contains a second beneficialagent formulation. The first and second beneficial agent formulationeach comprises a different beneficial agent, and the first and seconddevice each delivers an amount of beneficial agent to provide effective,therapeutic treatment for the one or more disease or condition. In someembodiments, the first and second beneficial agent both treat the samedisease or condition. In other embodiments, the first and secondbeneficial agents treat different diseases or conditions.

The invention also includes a kit for use in practicing a treatmentmethod of the present invention, wherein the kit provides the osmoticdevice(s) and may comprise further components as well.

In another aspect the invention includes methods of manufacturing theosmotic delivery devices of the present inventions and kits comprisingosmotic delivery devices.

These and other embodiments of the present invention will readily occurto those of ordinary skill in the art in view of the disclosure herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 presents a partial cross-sectional view of one embodiment of anosmotic delivery device useful in the practice of the present invention.

FIG. 2 presents a schematic diagram representing the delivery of two,layered beneficial agent formulations from a single osmotic deliverydevice. The dose or amount of the beneficial agent being delivered inshown on the Y axis and the time period over which the beneficial agentsare delivered is shown on the X axis.

FIG. 3A illustrates a side view of a multiple channel osmotic deliverydevice. FIG. 3B illustrates and end view of FIG. 3A. FIG. 3C illustratesand end view of a diffusion moderator component of a multiple channelosmotic delivery device. FIG. 3D illustrates a side view of a diffusionmoderator component of a multiple channel osmotic delivery device.

FIG. 4A illustrates a side view osmotic delivery device comprising twochannels. FIG. 4B illustrates the relationship of the two channelswithin a larger diameter columnar structure and shows a cross sectionalarea at the dashed line of FIG. 4A.

FIG. 5A illustrates a side view of an osmotic delivery device having afirst beneficial agent reservoir within a second beneficial agentreservoir, wherein the first beneficial agent reservoir and the secondbeneficial agent reservoir are essentially concentric. FIG. 5Billustrates a cross-section of the semi-permeable membrane end (FIG. 5A,501) of the device. FIG. 5C illustrates an end view of the diffusionmoderator end (FIG. 5A, 502) of the device. FIG. 5D illustrates across-sectional view of a diffusion moderator of the device presentingan example of a donut-like relationship for the diffusion moderator ofthe outer reservoir relative to the inner reservoir. An illustration ofa flow path is shown in FIG. 5E.

FIG. 6 illustrates a device for dual osmotic delivery that has centrallylocated semi-permeable membranes for fluid imbibition and distallylocated diffusion moderators for release of the beneficial agentformulations.

FIG. 7A illustrates a device for dual osmotic delivery that hascentrally located diffusion moderators for release of the beneficialagent formulations and distally located semi-permeable membranes forfluid imbibition. FIG. 7B illustrates an example of a single-componentdiffusion moderator for use with the device.

DETAILED DESCRIPTION

All patents, publications, and patent applications cited in thisspecification are herein incorporated by reference as if each individualpatent, publication, or patent application was specifically andindividually indicated to be incorporated by reference in its entiretyfor all purposes.

The figures illustrating osmotic devices and their components are forillustrative purposes and are not drawn to scale.

1.0 DEFINITIONS

It is to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting. As used in this specification and the appended claims,the singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a solvent” includes a combination of two or more such solvents,reference to “a peptide” includes one or more peptides, mixtures ofpeptides, and the like.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains. Although other methods andmaterials similar, or equivalent, to those described herein can be usedin the practice of the present invention, the preferred materials andmethods are described herein.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

The terms “peptide,” “polypeptide,” and “protein” are usedinterchangeable herein and typically refer to a molecule comprising achain of two or more amino acids (e.g., most typically L-amino acids,but also including, e.g., D-amino acids, modified amino acids, aminoacid analogues, and/or amino acid mimetic). Peptides may also compriseadditional groups modifying the amino acid chain, for example,functional groups added via post-translational modification. Examples ofpost-translation modifications include, but are not limited to,acetylation, alkylation (including, methylation), biotinylation,glutamylation, glycylation, glycosylation, isoprenylation, lipoylation,phosphopantetheinylation, phosphorylation, selenation, and C-terminalamidation. The term peptide also includes peptides comprisingmodifications of the amino terminus and/or the carboxy terminus.Modifications of the terminal amino group include, but are not limitedto, des-amino, N-lower alkyl, N-di-lower alkyl, and N-acylmodifications. Modifications of the terminal carboxy group include, butare not limited to, amide, lower alkyl amide, dialkyl amide, and loweralkyl ester modifications (e.g., wherein lower alkyl is C₁₋₄ alkyl).

The terminal amino acid at one end of the peptide chain typically has afree amino group (i.e., the amino terminus). The terminal amino acid atthe other end of the chain typically has a free carboxyl group (i.e.,the carboxy terminus). Typically, the amino acids making up a peptideare numbered in order, starting at the amino terminus and increasing inthe direction of the carboxy terminus of the peptide.

The phrase “amino acid residue” as used herein refers to an amino acidthat is incorporated into a peptide by an amide bond or an amide bondmimetic.

The term “vehicle” as used herein refers to a medium used to carry acompound. Vehicles of the present invention typically comprisecomponents such as polymers and/or solvents. In one embodiment, thevehicle of the present invention is a suspension vehicle. A typicalsuspension vehicle comprises solvents and polymers in which polypeptideparticles are suspended.

The phrase “phase separation” as used herein refers to the formation ofmultiple phases (e.g., liquid or gel phases) in the vehicle, for examplewhen a suspension vehicle contacts the aqueous environment. In someembodiments of the present invention, a suspension vehicle is formulatedto exhibit phase separation upon contact with an aqueous environmenthaving less than approximately 10% water.

The phrase “single-phase” as used herein refers to a solid, semisolid,or liquid homogeneous system that is physically and chemically uniformthroughout.

The term “dispersed” as used herein refers to dissolving, dispersing,suspending, or otherwise distributing a compound in a vehicle. In oneembodiment, a peptide or polypeptide particle is suspended in asuspension vehicle. In another embodiment, a beneficial agent isdissolved in a vehicle or in the same suspension vehicle as apolypeptide particle is suspended.

The phrase “chemically stable” as used herein refers to formation in aformulation of an acceptable percentage of degradation products,including degradation products from the beneficial agents, produced overa defined period of time by chemical pathways, such as deamidation,(usually by hydrolysis), aggregation, oxidation, or reactions with otherchemicals.

The phrase “physically stable” as used herein refers to formation in aformulation of an acceptable percentage of aggregates (e.g., dimers andother higher molecular weight products) of beneficial agents. Further, aphysically stable formulation does not change its physical state as, forexample, from liquid to solid, from amorphous to crystal form, or fromone crystal form to another.

The term “viscosity” as used herein typically refers to a valuedetermined from the ratio of shear stress to shear rate (e.g.,Considine, D. M. & Considine, G. D., Encyclopedia of Chemistry, 4thEdition, Van Nostrand, Reinhold, N.Y., 1984) essentially as follows:

F/A=μ*V/L  (1)

where F/A is shear stress (force per unit area), μ is a proportionalityconstant (viscosity), and V/L is the velocity per layer thickness (shearrate).

From this relationship, the ratio of shear stress to shear rate definesviscosity. Measurements of shear stress and shear rate are typicallydetermined using parallel plate rheometery performed under selectedconditions (for example, a temperature of about 37° C.). Other methodsfor the determination of viscosity include, measurement of a kinematicviscosity using a viscometer, for example, a Cannon-Fenske viscometer, aUbbelohde viscometer for the Cannon-Fenske opaque solution, or a Ostwaldviscometer. Generally, vehicles of the present invention have aviscosity sufficient to prevent a particle formulation or beneficialagent dispersed therein from settling during storage and use in a methodof delivery, for example, in an implantable, drug delivery device.

The term “non-aqueous” as used herein refers to an overall moisturecontent, for example, of a formulation, of a suspension formulation,typically of less than or equal to about 15 wt %, preferably of lessthan or equal to about 10 wt %, preferably less than or equal to about 7wt %, more preferably less than or equal to about 5 wt %, and morepreferably less than about 4 wt %.

The term “subject” as used herein refers to any member of the subphylumChordata, including, without limitation, humans and other primates,including non-human primates such as rhesus macaques, cynomolgusmonkeys, and other monkey species and chimpanzees and other ape species;farm animals such as cattle, sheep, pigs, goats and horses; domesticmammals such as dogs and cats; laboratory animals including rodents suchas mice, rats and guinea pigs; birds, including domestic, wild and gamebirds such as chickens, turkeys and other gallinaceous birds, ducks,geese, and the like. The term does not denote a particular age. Thus,both adult and newborn subjects are included.

The phrase “concurrent delivery” as used herein describes simultaneous,contemporaneous, parallel, or concomitant administration of two or morebeneficial agents, wherein the two or more beneficial agents areadministered to the same subject over a period of time (e.g., about twoweeks, about four weeks, about six weeks, about eight weeks, about threemonths, about six months, or up to about a year).

The terms “drug,” “therapeutic agent,” “active agent” and “beneficialagent” are used interchangeably to refer to any therapeutically activesubstance that is delivered to a subject to produce a desired beneficialeffect. In one embodiment of the present invention, the drug is protein,for example, an interferon or an insulinotropic peptide. In anotherembodiment of the present invention, the drug is a small molecule, forexample, steroid hormones such as androgens or estrogens. Examples ofnumerous beneficial agents are presented herein.

The term “interferon” as used herein includes, but is not limited to,the three major classes of human interferons (e.g., The Interferons:Characterization and Application, by Anthony Meager (Editor), Wiley-VCH(May 1, 2006)), as well as analogs, variants, and derivatives thereof,for example: Interferon type I (e.g., alpha interferon (includingalfa-2a and alfa-2b), beta interferon (including beta-1a and beta1-b),omega interferon, tau interferon; Interferon type II (e.g., gammainterferon), and Interferon type III (e.g., lambda interferon). Further,the term refers to a variety of consensus interferons (e.g., U.S. Pat.Nos. 4,695,623, 4,897,471, 5,372,808, 5,541,293, and 6,013,253).

The term “insulinotropic” as used herein refers to the ability of acompound, e.g., a peptide, to stimulate or affect the production and/oractivity of insulin (e.g., an insulinotropic hormone). Such compoundstypically stimulate the secretion or biosynthesis of insulin in asubject.

The phrase “insulinotropic peptide” as used herein includes, but is notlimited to, glucagon-like peptide 1 (GLP-1), as well as analogs,variants, and derivatives thereof, and exendin-4, as well as analogs,variants, and derivatives thereof.

The term “osmotic delivery device” as used herein typically refers to adevice used for delivery of one or more beneficial agent to a subject,wherein the device comprises, for example, a reservoir (made, forexample, from a titanium alloy) having a lumen that contains, in onechamber, a beneficial agent formulation (e.g., comprising one or morebeneficial agent) and, in another chamber, an osmotic agent formulation.A piston assembly positioned in the lumen isolates the beneficial agentformulation from the osmotic agent formulation. A semi-permeablemembrane is positioned at a first distal end of the reservoir adjacentthe osmotic agent formulation. A diffusion moderator (which defines adelivery orifice through which the beneficial agent formulation exitsthe device) is positioned at a second distal end of the reservoiradjacent the suspension formulation. The piston assembly and thediffusion moderator define a chamber that contains the beneficial agentformulation and the piston assembly and the semipermeable membranedefine a chamber that contains the osmotic agent formulation. The terms“flow modulator,” “diffusion modulator,” “flow moderator,” and“diffusion moderator” are used interchangeably herein. Typically, theosmotic delivery device is implanted within the subject, for example,subcutaneously (e.g., in the inside, outside, or back of the upper arm;or in the abdominal area). An exemplary osmotic delivery device is theDUROS™ delivery device.

2.0 GENERAL OVERVIEW

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particular beneficialagents, particular types of drug delivery devices, particular sources ofbeneficial agents, particular solvents, particular polymers, and thelike, as use of such particulars may be selected in view of theteachings of the present specification. It is also to be understood thatthe terminology used herein is for the purpose of describing particularembodiments of the invention only, and is not intended to be limiting.Drawings of the devices are not to scale and are intended to provideschematic representation of the components of the device as well asgeneral spatial relationships.

When describing components, for example, chambers, of an osmoticdelivery device, sub scripted numbers are typically used to distinguishchambers associated with other components, for example, a first pistonthat divides a first reservoir into a first₂ and a second₁ chamber.

In one aspect, the present invention relates to osmotic delivery devicescomprising multiple beneficial agent chambers. In one embodiment, thepresent invention relates to a dual osmotic delivery device. This dualdevice comprises a first osmotic delivery device contained within asecond osmotic delivery device, wherein each osmotic delivery devicecomprises an impermeable reservoir that defines a lumen and two ends.The diameter of the lumen of the second device is greater than thediameter of the lumen of the first device. The ends of the first and thesecond device are substantially coincident and each end of the firstosmotic delivery device is substantially concentric in relationship to acorresponding end of the second delivery device. The first osmoticdelivery device, having an inner and an outer surface, comprises thefollowing components: a first impermeable reservoir; a first piston thatdivides the first reservoir into a first₁ and a second₁ chamber andisolates the first₁ chamber from the second₁ chamber; a first osmoticagent formulation in the first₁ chamber; a first beneficial agentformulation in the second₁ chamber; a first semi-permeable membrane insealing relationship with the open end of the first₁ chamber; and afirst diffusion moderator in mating relationship with the open end ofthe second₁ chamber, wherein the diffusion moderator defines an orificethrough which the first beneficial agent is capable of exiting the firstdevice, and the first diffusion moderator effectively isolates the firstbeneficial agent formulation within the second₁ chamber from theenvironment of use. The second osmotic delivery device, having an innerand an outer surface, comprises the following components: a secondpiston that divides the second reservoir into a first₂ and a second₂chamber, wherein the second piston (i) contacts the inner surface of thesecond reservoir in sealing relationship, and (ii) defines an internalopening that contacts the outer surface of the first reservoir insealing relationship, thus isolating the first₂ chamber from the second₂chamber; a second osmotic agent formulation in the first₂ chamber; asecond beneficial agent formulation in the second₂ chamber; a secondsemi-permeable membrane in sealing relationship with the open end of thesecond₂ chamber, wherein the second semi-permeable membrane contacts theouter surface of the first reservoir in sealing relationship; and asecond diffusion moderator in mating relationship with the open end ofthe second₂ chamber, wherein (i) the second diffusion moderator (a)defines an orifice through which the second beneficial agent is capableof exiting the device, and (b) contacts the outer surface of the firstreservoir in sealing relationship, and (ii) the second diffusionmoderator effectively isolates the second beneficial agent formulationwithin the second₂ chamber from the environment of use.

In a second embodiment, the present invention relates to a dual osmoticdelivery device, comprising first and second osmotic delivery devices.This dual device comprises an impermeable reservoir having outer andinner surfaces and first and second ends, wherein the reservoir (i)defines a lumen between the first and second ends, and at least oneopening between the inner and outer surface, and (ii) the opening islocated approximately half-way between the first and second ends. Thefirst osmotic delivery device comprises the following components: afirst reservoir portion extending from the first end of the reservoir toadjacent the opening; a first piston that divides the first reservoirportion into a first₁ and a second₁ chamber, and isolates the first₁chamber from the second₁ chamber, wherein the first₁ chamber is adjacentthe opening; a first osmotic agent formulation in the first₁ chamber; afirst beneficial agent formulation in the second₁ chamber; a firstsemi-permeable membrane in sealing relationship with the open end of thefirst₁ chamber, wherein the first semi-permeable membrane is adjacentthe opening and isolates the first₁ chamber from the opening; and afirst diffusion moderator in mating relationship with the open end ofthe second₁ chamber, wherein (i) the diffusion moderator defines anorifice through which the first beneficial agent is capable of exitingthe second₁ chamber, and (ii) the first diffusion moderator effectivelyisolates the first beneficial agent formulation within the second₁chamber from the environment of use. The second osmotic delivery devicecomprises the following components: a second reservoir portion extendingfrom the second end of the reservoir to adjacent the opening; a secondpiston that divides the second reservoir portion into a first₂ and asecond₂ chamber, and isolates the first₂ chamber from the second₂chamber, wherein the first₂ chamber is adjacent the opening; a secondosmotic agent formulation in the first₂ chamber; a second beneficialagent formulation in the second₂ chamber; a second semi-permeablemembrane in sealing relationship with the open end of the first₂chamber, wherein the second semi-permeable membrane is adjacent theopening and isolates the first₂ chamber from the opening; and a seconddiffusion moderator in mating relationship with the open end of thesecond₂ chamber, wherein the diffusion moderator defines an orificethrough which the second beneficial agent is capable of exiting thesecond₂ chamber, wherein the second diffusion moderator effectivelyisolates the second beneficial agent formulation within the second₂chamber from the environment of use. In this dual device the firstsemi-permeable membrane and the second semi-permeable membrane define afluid imbibition chamber that includes a portion of the reservoir thatdefines the opening.

In a third embodiment, the present invention relates to a dual osmoticdelivery device, comprising first and second osmotic delivery devices.This dual device comprises an impermeable reservoir having outer andinner surfaces and first and second ends, wherein the reservoir (i)defines a lumen between the first and second ends, (ii) defines at leasttwo openings between the inner and outer surface, and (iii) the openingsare located approximately half-way between the first and second ends.The first device comprises the following components: a first reservoirportion extending from the first end of the reservoir to adjacent theopenings; a first piston that divides the first reservoir portion into afirst₁ and a second₁ chamber, wherein the piston isolates the first₁chamber from the second₁ chamber, and the second₁ chamber is adjacentthe openings; a first osmotic agent formulation in the first₁ chamber; afirst beneficial agent formulation in the second₁ chamber; a firstsemi-permeable membrane in sealing relationship with the open end of thefirst₁ chamber; and a first diffusion moderator in mating relationshipwith the open end of the second₁ chamber, wherein the diffusionmoderator defines an orifice through which the first beneficial agent iscapable of exiting the second₁ chamber, the orifice is aligned with oneof the openings in the reservoir, and the first diffusion moderatoreffectively isolates the first beneficial agent formulation within thesecond₁ chamber from the environment of use. The second osmotic deliverydevice comprises the following components: a second reservoir portionextending from the second end of the reservoir to adjacent the openings;a second piston that divides the second reservoir portion into a first₂and a second₂ chamber, wherein the piston isolates the first₂ chamberfrom the second₂ chamber, and the second₂ chamber is adjacent theopenings; a second osmotic agent formulation in the first₂ chamber; asecond beneficial agent formulation in the second₂ chamber; a secondsemi-permeable membrane in sealing relationship with the open end of thefirst₂ chamber; and a second diffusion moderator in mating relationshipwith the open end of the second₂ chamber, wherein the diffusionmoderator defines an orifice through which the second beneficial agentis capable of exiting the second₂ chamber, the orifice is aligned withthe second opening in the reservoir, and the diffusion moderatoreffectively isolates the second beneficial agent formulation within thesecond₂ chamber from the environment of use.

In a fourth embodiment, the present invention relates to a dual osmoticdelivery device, comprising first and second osmotic delivery devices.The first osmotic delivery device comprises the following components: afirst impermeable reservoir having a first open end and a second openend; a first piston that divides the first reservoir into a first₁ and asecond₁ chamber, wherein the piston isolates the first₁ chamber from thesecond₁ chamber; a first osmotic agent formulation in the first₁chamber; a first beneficial agent formulation in the second₁ chamber; afirst semi-permeable membrane in sealing relationship with the open endof the first₁ chamber; and a diffusion moderator in mating relationshipwith the open end of the second₁ chamber, wherein the diffusionmoderator defines a first orifice through which the first beneficialagent is capable of exiting the second₁ chamber, and the diffusionmoderator effectively isolates the first beneficial agent formulationwithin the second₁ chamber from the environment of use. The secondosmotic delivery device comprises the following components: a secondimpermeable reservoir having a first open end and a second open end; asecond piston that divides the second reservoir portion into a first₂and a second₂ chamber, wherein the piston isolates the first₂ chamberfrom the second₂ chamber; a second osmotic agent formulation in thefirst₂ chamber; a second beneficial agent formulation in the second₂chamber; and a second semi-permeable membrane in sealing relationshipwith the open end of the first₂ chamber. In this embodiment, thediffusion moderator is in mating relationship with the open end of thesecond₂ chamber, wherein the diffusion moderator defines a secondorifice through which the second beneficial agent is capable of exitingthe second₂ chamber, and the diffusion moderator effectively isolatesthe second beneficial agent formulation within the second₂ chamber fromthe environment of use.

In a fifth embodiment, the present invention relates to a dual osmoticdelivery device, comprising an impermeable reservoir having outer andinner surfaces and first and second ends, wherein the reservoir definesa first chamber adjacent the first end of the reservoir in fluidcommunication with second and third essentially columnar chambers thatextend to the second end of the reservoir each of the second and thirdchambers defining an open end, wherein each set of the first chamber andsecond chamber, and the first chamber and the third chamber defines aflow path through the reservoir. A first piston and a second piston arelocated in the second and third chambers, respectively, wherein thepistons isolate the first chamber from the second and third chambers. Anosmotic agent formulation is present in the first chamber. Asemi-permeable membrane is positioned in sealing relationship with theopen end of the first chamber. A first beneficial agent formulation ispresent in the second chamber, and a second beneficial agent formulationin the third chamber. A diffusion moderator is positioned in matingrelationship with the end of the reservoir, wherein the diffusionmoderator defines a first orifice through which the first beneficialagent is capable of exiting the second chamber, and a second orificethrough which the second beneficial agent is capable of exiting thethird chamber. The diffusion moderator effectively isolates the firstand second beneficial agent formulations, within, respectively, thesecond and third chambers, from the environment of use.

In a sixth embodiment, the present invention relates to a multipleosmotic delivery device, comprising at least two and preferably three ormore beneficial agent chambers. In one embodiment, this multiple osmoticdelivery device comprises three beneficial agent chambers. This multipleosmotic delivery device comprises an impermeable reservoir having firstand second ends, wherein the reservoir defines at least first, secondand third essentially columnar hollow tubes that extend from the firstend of the reservoir to the second end of the reservoir, each of thefirst, second and third essentially columnar hollow tube defining afirst open end and a second open end. The first osmotic delivery devicecomprises the following components: a first piston that divides thefirst columnar tube into a first₁ and a second₁ chamber, wherein thepiston isolates the first₁ and second₁ chambers; a first osmotic agentformulation in the first₁ chamber; a first beneficial agent formulationin the second₁ chamber; a first semi-permeable membrane in sealingrelationship with the first open end of the first₁ chamber; and adiffusion moderator in mating relationship with the second open end ofthe second₁ chamber, wherein the diffusion moderator defines an orificethrough which the first beneficial agent is capable of exiting thesecond₁ chamber, and the diffusion moderator effectively isolates thefirst beneficial agent formulation within the second₁ chamber from theenvironment of use. The second osmotic delivery device comprises thefollowing components: a second piston that divides the second columnartube into a first₂ and a second₂ chamber, wherein the piston isolatesthe first₂ and second₂ chambers; a second osmotic agent formulation inthe first₂ chamber; a second beneficial agent formulation in the second₂chamber; a second semi-permeable membrane in sealing relationship withthe first open end of the first₂ chamber; and a diffusion moderator inmating relationship with the second open end of the second₂ chamber,wherein the diffusion moderator defines an orifice through which thesecond beneficial agent is capable of exiting the second₂ chamber, andthe diffusion moderator effectively isolates the second beneficial agentformulation within the second₂ chamber from the environment of use. Thethird osmotic delivery device comprises the following components: athird piston that divides the third columnar tube into a first₃ and asecond₃ chamber, wherein the piston isolates the first₃ and second₃chambers; a third osmotic agent formulation in the first₃ chamber; athird beneficial agent formulation in the second₃ chamber; a thirdsemi-permeable membrane in sealing relationship with the first open endof the first₃ chamber; and a diffusion moderator in mating relationshipwith the second open end of the second₃ chamber, wherein the diffusionmoderator defines an orifice through which the third beneficial agent iscapable of exiting the second₃ chamber, and the diffusion moderatoreffectively isolates the third beneficial agent formulation within thesecond₃ chamber from the environment of use.

The reservoir of the osmotic delivery devices of the present inventioncan be made of number of substantially impermeable materials. Inpreferred embodiments, the reservoir is made of titanium or a titaniumalloy.

In the osmotic delivery systems of the present invention, the osmoticagent formulation may be the same in all osmotic formulation chambers ordifferent formulations may be used in different chambers.

In some embodiments, each beneficial agent chamber contains a beneficialagent formulation comprising a single beneficial agent and a vehicle,typically a viscous vehicle. In other embodiments of the presentinvention, at least one beneficial agent chamber contains a beneficialagent formulation comprising two or more beneficial agents and avehicle, typically a viscous vehicle. When the beneficial agentformulation comprises two or more beneficial agents and a viscousvehicle, examples of combined formulations include, but are not limitedto, the following: (i) two or more beneficial agents dispersed directlyin the vehicle; (ii) one or more beneficial agent dispersed directly inthe vehicle and one or more beneficial agent formulated into a particleformulation that is suspended in the vehicle; (iii) two or morebeneficial agents combined in one particle formulation and the particleformulation suspended in the vehicle; and (iv) two or more beneficialagents formulated individually into different particle formulations andthe different particle formulations suspended together in the vehicle.

In another aspect the present invention relates to combined beneficialagent formulations. Examples of such beneficial agent formulationsinclude, but are not limited to, the following: (i) two or morebeneficial agents dispersed directly in the vehicle; (ii) one or morebeneficial agent dispersed directly in the vehicle and one or morebeneficial agent formulated into a particle formulation that issuspended in the vehicle; (iii) two or more beneficial agents combinedin one particle formulation and the particle formulation suspended inthe vehicle; and (iv) two or more beneficial agents formulatedindividually into different particle formulations and the differentparticle formulations suspended together in the vehicle. In oneembodiment, this aspect of the present invention relates to an osmoticdelivery device comprising a beneficial agent chamber containing two ormore beneficial agents. The beneficial agent chamber typically containsa beneficial agent formulation comprising two or more beneficial agentsand a viscous vehicle.

In some embodiments of the combined beneficial agent formulations of thepresent invention, at least one beneficial agent is a small molecule andat least one beneficial agent is a polypeptide, in other embodiments atleast two beneficial agents are polypeptides, and in other embodimentsat least two beneficial agents are small molecules. When the combinedbeneficial agent formulation comprises at least two polypeptides, theformulation may comprise the polypeptides in a variety of ways,including, but not limited to, the following: at least one of thepolypeptides may be dissolved in the vehicle; at least one of thepolypeptides may be formulated into a particle formulation that issuspended in the vehicle; at least two polypeptides may be formulatedinto one particle formulation that is suspended in the vehicle; a firstpolypeptide may be formulated into a first particle formulation and asecond polypeptide may be formulated into a second particle formulation,and the first and second particle formulations are suspended in thevehicle (and so on for additional proteins); and combinations thereof.

In one embodiment of the present invention, a first polypeptide isexendin-4, a second polypeptide is oxyntomodulin or PYY, wherein two ofthe polypeptides are formulated into one particle formulation or thepolypeptides are separately formulated into individual particleformulations (e.g., Examples 1-4). In another embodiment of the presentinvention, a first particle formulation comprises one or morepolypeptide (e.g., interferon) and a second formulation comprises asmall molecule (e.g., Amphotericin B) in a formulation (e.g., suspensionformulation or solution formulation). In another embodiment of thepresent invention, a first polypeptide is amylin and a secondpolypeptide is leptin, wherein the polypeptides are both formulated intoone particle formulation or the polypeptides are separately formulatedinto individual particle formulations (e.g., one particle formulationcomprising amylin and a second particle formulation comprising leptin).

In another aspect, the present invention relates to a method of treatinga disease or condition in a subject in need of treatment, comprisingproviding a dual or multiple osmotic delivery device of the presentinvention to the subject, wherein the osmotic delivery device delivers atherapeutically effective amount of two or more beneficial agents totreat the disease or condition. The dual or multiple osmotic deliverydevice is implanted in the subject. One or more such dual or multipleosmotic delivery device may be implanted.

In another embodiment, the present invention relates to a method oftreating two or more diseases or conditions in a subject in need oftreatment, comprising providing a dual or multiple osmotic deliverydevice of the present invention to the subject, wherein the osmoticdelivery device delivers a therapeutically effective amount of (i) oneor more beneficial agent to treat a first disease or condition, and (ii)one or more beneficial agent to treat a second disease or condition. Thedual or multiple osmotic delivery device is implanted in the subject.One or more such dual or multiple osmotic delivery device may beimplanted.

In another aspect the present invention provides a method of treatingone or more disease or condition in a subject in need of treatment. Inthis method a first osmotic delivery device is provide comprising afirst beneficial agent chamber that contains a first beneficial agentformulation, and a second osmotic delivery device is provided comprisinga second beneficial agent chamber that contains a second beneficialagent formulation. The first and second beneficial agent formulationeach comprises a different beneficial agent, and the first and seconddevice each delivers an amount of beneficial agent to provide effective,therapeutic treatment for the one or more disease or condition. In someembodiments, the first and second beneficial agent both treat the samedisease or condition. In some embodiments of the present invention, thefirst beneficial agent is exendin-4, the second beneficial agent isoxyntomodulin or PYY, and the method of treating facilitates or promotesweight loss. In another embodiment of the present invention, the firstbeneficial agent is exendin-4, the second beneficial agent isoxyntomodulin, and the third beneficial agent is PYY, and the method oftreating facilitates or promotes weight loss. In another embodiment ofthe present invention, the first beneficial agent is amylin, the secondbeneficial agent is leptin, and the method of treating facilitates orpromotes weight loss. In other embodiments, the first and secondbeneficial agents treat different diseases or conditions.

The invention also includes a kit for use in practicing a treatmentmethod of the present invention, wherein the kit provides the osmoticdevice(s) and may comprise further components as well. In oneembodiment, the kit of the present invention provides at least a firstosmotic delivery device, comprising a first beneficial agent chamberthat contains a first beneficial agent formulation, and a second osmoticdelivery device, comprising a second beneficial agent chamber thatcontains a second beneficial agent formulation, wherein the first andsecond beneficial agent formulation each comprises a differentbeneficial agent.

The present invention also includes methods of manufacturing the osmoticdelivery devices and kits of the present invention. Methods ofmanufacturing typically include positioning and assembling thecomponents of the osmotic delivery devices into functional relationship,as well as assembly of the components of the kit. Kits are typicallysterile and may be sterilized and kept sterile by a variety of meansknown in the art.

These aspects and embodiments of the invention are described in detailwith reference to some preferred embodiments, as illustrated, forexample, in the accompanying drawings. In describing some preferredembodiments herein below, numerous specific details are set forth inorder to provide a thorough understanding of the invention. However, itwill be apparent to one skilled in the art that the invention may bepracticed without some or all of these specific details. In otherinstances, well-known features and/or process steps have not beendescribed in detail so as not to unnecessarily obscure the invention. Inaddition, like or identical reference numerals are used to identifycommon or similar elements.

2.1 Devices for Use in the Practice of the Present Invention

In one aspect, the present invention relates to the use of osmoticdelivery devices for the delivery of two or more beneficial agents. Insome embodiments, two or more delivery devices are used wherein thedevices are typically implanted at one or more location in the body of asubject. In other embodiments, a single device is used for the deliveryof multiple beneficial agent formulations, wherein the device isimplanted at a single location within the body of a subject.

Some osmotic delivery devices and their component parts have beendescribed, for example, the DUROS™ delivery device or similar devices(e.g., U.S. Pat. Nos. 5,609,885, 5,728,396, 5,985,305, 5,997,527,6,113,938, 6,132,420, 6,156,331, 6,217,906, 6,261,584, 6,270,787,6,287,295, 6,375,978, 6,395,292, 6,508,808, 6,524,305, 6,544,252,6,635,268, 6,682,522, 6,923,800, 6,939,556, 6,976,981, 6,997,922,7,014,636, 7,074,423, 7,207,982, 7,112,335, 7,163,688, and 7,241,457;U.S. Patent Publication Nos. 2005-0175701, 2007-0281024, 2008-0091176).

The DUROS™ device releases a beneficial agent at a predetermined ratebased on the principle of osmosis. Extracellular fluid (e.g., from thefluid environment into which the device was placed, for example, byimplantation in a subject) enters the DUROS™ device through asemi-permeable membrane directly into an osmotic engine (e.g., a chambercomprising an osmotic agent formulation) that expands to drive thepiston at a slow and even delivery rate. Movement of the piston forcesthe beneficial agent formulation to be released through the orifice orexit port.

Implantable devices, for example, the DUROS™ device, provide thefollowing advantages for administration of beneficial agentformulations: true zero-order release of the beneficial agentpharmacokinetically; long-term release period time (e.g., up to about ayear); and reliable delivery and dosing of a beneficial agent.

FIG. 1 depicts an example of an osmotic delivery system useful in thepractice of the present invention. In FIG. 1, an osmotic delivery device10 is shown comprising a reservoir 12. A piston assembly 14 ispositioned in the lumen of the reservoir and divides the lumen into twochambers. In this example, the chamber 16 contains a beneficial agentformulation and the chamber 20 contains an osmotic agent formulation. Asemi-permeable membrane 18 is positioned at a distal end of thereservoir, adjacent the chamber 20 containing the osmotic agentformulation. A diffusion moderator 22 is positioned in matingrelationship at a distal end of the reservoir 12, adjacent the chamber16 containing the beneficial agent formulation. The diffusion moderator22 includes a delivery orifice 24. The diffusion moderator 22 may be anysuitable flow device having a delivery orifice. In this embodiment, theflow path 26 is formed between a threaded diffusion moderator 22 andthreads 28 formed on the interior surface of the reservoir 12. Inalternative embodiments, the diffusion moderator can, for example, (i)be press-fit (or friction fit) through an opening and contacting asmooth interior surface of the reservoir, or (ii) comprise two pieceswith an outer shell constructed and arranged for positioning in anopening, an inner core inserted in the outer shell, and a fluid channelhaving a spiral shape defined between the outer shell and the inner core(e.g., U.S. Patent Publication No. 2007-0281024).

Fluid is imbibed into the chamber 20 through the semi-permeable membrane18. The beneficial agent formulation is dispensed from the chamber 16through the delivery orifice 24 in the diffusion moderator 22. Thepiston assembly 14 engages and seals against the interior wall of thereservoir 12, thereby isolating the osmotic agent formulation in chamber20 and fluid imbibed through the semi-permeable membrane 18 from thebeneficial agent formulation in chamber 16. At steady-state, thebeneficial agent formulation is expelled through the delivery orifice 24in the diffusion moderator 22 at a rate corresponding to the rate atwhich external fluid is imbibed into the chamber 20 through thesemi-permeable membrane 18.

The semi-permeable membrane 18 may be in the form of a plug that isresiliently engaged in sealing relationship with the interior surface ofthe reservoir 12. In FIG. 1, it is shown to have ridges that serve tofrictionally engage the semi-permeable membrane 18 with the interiorsurface of the reservoir 12.

In view of the teachings of the present specification, one of ordinaryskill in the art can select the appropriate number and type of osmoticdelivery devices for use in the methods of the present invention.

2.1.1 Devices Comprising a Single Beneficial Agent Formulation Chamber

In one embodiment of the present invention, two or more osmotic deliverydevices, each having a single beneficial agent chamber (e.g., as shownin FIG. 1), are implanted in a subject at one or more locations. Forexample, two delivery devices are implanted in a subject, the firstdevice containing a formulation comprising a first beneficial agent, anda second device containing a formulation comprising a second beneficialagent. For example, one device may be implanted subcutaneously in theupper left arm and the second device implanted subcutaneously in theupper right arm, or one device may be implanted subcutaneously in thelower left abdomen and the second device implanted subcutaneously in thelower right abdomen.

Examples of formulations and beneficial agents are discussed hereinbelow. Two or more osmotic delivery devices, each having a singlebeneficial agent chamber, may comprise the same or different beneficialagent in a formulation to achieve, for example, delivery of the samebeneficial agent for different duration (i.e., different periods oftime), or to achieve differential dosing over time, for example, astep-down dosing (e.g., wherein the beneficial agent in a first deviceis depleted before the beneficial agent in the second device), or astep-up dosing (e.g., wherein the first device delivers the beneficialagent over a period of time and the second device begins delivery of thebeneficial agent at a later time than the first device or is implantedat a later time). Step-down and step-up dosing methods are discussedfurther herein below. Further, two or more osmotic delivery deviceshaving single beneficial agent chambers may be used to deliver two ormore different beneficial agents, wherein the two or more beneficialagents are used for the treatment of one or more disease or condition.For example, a first osmotic delivery device, comprising exendin-4, anda second delivery device, comprising a oxyntomodulin or PYY, can both beimplanted in a subject to facilitate or promote weight loss, forexample, in obese or overweight subjects. As another example, a firstosmotic delivery device, comprising amylin, and a second deliverydevice, comprising a leptin, can both be implanted in a subject tofacilitate or promote weight loss, for example, in obese or overweightsubjects.

Two or more osmotic delivery devices comprising two or more differentbeneficial agents may be provided in a kit for the treatment of one ormore disease or condition. Further, the kit may include one or more ofthe following: instructions; a topical anesthetic (e.g., 10 ml ampule 2%lidocaine); assorted surgical tools and accessories (e.g., forceps,hemostat clamp, surgical drape(s), povidone iodine swab(s), syringe(s),needle(s), surgical blade(s) and handle, gauze sponge(s), skinprotectant, wound closure strip(s), adhesive bandage(s), alcohol pad(s),marking pen, and ruler); and an implantor device (e.g., U.S. Pat. No.6,190,350).

In a second embodiment of the present invention, a single osmoticdelivery device having a single beneficial agent chamber is implanted ina subject, wherein the single device contains a formulation comprisingtwo or more beneficial agents. Examples of such formulations aredescribed further herein below (“Combined Formulations”).

In a third embodiment of the present invention, a single osmoticdelivery device having a single beneficial agent chamber is implanted inthe subject, wherein two or more beneficial agent formulations arealternately layered within the beneficial agent chamber of the osmoticdelivery device such that delivery of each beneficial agent occurs for aperiod of time followed by delivery of the second beneficial agent,etc., creating a cycle of delivery of the beneficial agents. Thisresults in stratified layers of beneficial agents within the beneficialagent chamber. As the beneficial agent formulations are delivered asteady-state level of each agent is established over time with peakdoses (i.e., C_(max)) of the beneficial agents separated over time. Sucha delivery profile is schematically represented in FIG. 2.

The layers of beneficial agent formulations remain discrete by virtue ofviscous nature of the vehicle in which the beneficial agents areformulated.

In FIG. 2, beneficial agents A (curve shown as a solid line) and B(curve shown as a dashed line) are delivered sequentially. The top ofthe curve for each of agents A and B represents the C_(max). Thestraight line across the center of the graph represents the averagesteady state delivery dose of the two beneficial agents. The amplitudeof each curve is related to the amount of beneficial agent beingdelivered, the rate at which the beneficial agent formulation isdelivered, and the thickness of the layer of the beneficial agent in theosmotic device.

An example of the usefulness of this approach to delivery of multiplebeneficial agents is alternating delivery of two polypeptides whenco-administration of the two polypeptides can produce toxic effects. Forexample, administration of an interferon with a cytokine (e.g., IL-2),where the alternating delivery maintains therapeutic levels of the twopolypeptides but abates the toxic effects of the two polypeptides beingco-administered.

2.1.2 Devices Comprising Multiple Beneficial Agent Chambers

The osmotic delivery devices of the present invention having multiplebeneficial agent chambers typically deliver one beneficial agentformulation per delivery orifice. However, use of the combinedformulations described herein below expand the usefulness of the osmoticdelivery devices having multiple delivery orifices in terms of thenumber of beneficial agents that can be delivered from any given device.Thus, although the devices described herein are exemplified for use withtwo different beneficial agents, use of the combined formulationsdescribed herein in these devices is also an aspect of the presentinvention.

Further, each beneficial agent chamber of osmotic delivery devicescomprising two or more beneficial agent chambers (as described herein)can be used in similar ways as described above for delivery ofbeneficial agent from osmotic delivery devices having a singlebeneficial agent chamber (e.g., two or more devices, or stratificationof beneficial agent formulations), thus further expanding the uses ofthe devices comprising two or more beneficial agent chambers.

2.1.2.1 Multiple Channel Devices

In one embodiment of the present invention, a cylindrical tube is made(e.g., by boring a solid material such as titanium or a titanium alloy)to create multiple channels, for example, a three channel tube (FIG.3A). Each channel of the tube is then adapted with the above-describedcomponents of the osmotic device, including, for each channel, asemi-permeable membrane, an osmotic agent chamber, a piston, abeneficial agent chamber, a diffusion moderator, and an orifice. Eachthe beneficial agent formulation in each channel can comprise adifferent beneficial agent, or, in some embodiments, multiple channelsmay contain the same beneficial agent at the same or different dosageamounts or concentrations.

In FIG. 3A, an example of a three-channel reservoir 300 is illustrated.The first distal end of the tube 310 comprises three openings that areadapted to receive the semi-permeable membranes, each of the threechannels 330, 340, 350 comprises an osmotic agent chamber, a piston, anda beneficial agent chamber. The second distal end of the tube 320comprises three openings that are adapted to receive diffusionmoderators that each comprises an orifice.

Typically, all of the diffusion moderators are located at the samedistal end of device and all of the semi-permeable membranes are locatedat the opposite distal end of the device. In other embodiments, theorifice for each channel's diffusion moderator may be on the outer, sidesurface of the device near a distal end. Combinations of such locationsfor the diffusion moderator orifices can also be made.

Such devices may further comprise a cap-like structure (FIG. 3D, 370) atthe end of the device where the orifices of the diffusion moderators arelocated such that the cap creates a terminal diffusion moderatordefining a single exit orifice from the device when the cap-likestructure is in operative contact with the device. That is, the end ofthe device where the orifices of the diffusion moderators are locatedcreates an inner diffusion moderator surface (FIG. 3A, FIG. 3B, FIG. 3D,320), which is adjacent to a chamber (FIG. 3D, 380) into which thebeneficial agent formulations exit the device, which is adjacent to anouter diffusion moderator surface (FIG. 3C, FIG. 3D, 360) comprising asingle orifice (FIG. 3C, FIG. 3D, 390) through which the mixture ofbeneficial agents exits the cap-like structure. Typically such a cap ispositioned in mating relationship with the device and held in place by,for example, press-fit (i.e., interference fit) or complementarycontinuous helical threads/grooves. Alternatively, such a cap may be anintegral part of the overall structure of the reservoir. Means forholding cap in place (e.g., friction fit or thread and groove) are notshown in FIG. 3D.

Although this example is described with reference to three channels, asimilar two-channel device can be made as well as a similar devicehaving more than three channels. Devices of this type have the advantageof being a single implantable device useful for the delivery of, forexample, multiple beneficial agent formulations in the same vehicle aswell as multiple beneficial agent formulations in different vehicles.

Further, such devices have the advantage of being adapted to providedifferent flow rates for delivery of the beneficial agent formulationsin the different channels by, for example, using differentsemi-permeable material in one or more of the channels that each providedifferent rates of fluid imbibition into the osmotic agent chamber. Inaddition, osmotic agent formulations having different expansionproperties can be employed. For example, the osmotic agent formulationmay include one or more osmotic polymers. An osmotic polymer is ahydrophilic polymer that can imbibe aqueous fluids (such as biologicalfluids and water) and upon imbibing aqueous fluids expands to anequilibrium state and retains a significant portion of the imbibedfluid. Depending on the osmotic polymer that is selected, the polymercan expand to varying degrees, for example, about 2 to about 50 timesits initial volume. An osmotic polymer may or may not be cross-linked.Preferred osmotic polymers are hydrophilic polymers that are lightlycross-linked, such cross-links being formed by covalent or ionic bondsor residue crystalline regions after swelling. Osmotic polymers may be,for example, of plant, animal or synthetic origin.

In an alternative embodiment, an osmotic delivery device is formedhaving a single semi-permeable membrane, a single osmotic agent chamber,multiple channels in fluid communication with the osmotic agent chamber,a piston assembly in each channel, a beneficial agent chamber in eachchannel, and at least one diffusion moderator that defines a flow pathfrom each beneficial agent chamber to an exit orifice. An illustrationof such an embodiment is presented in FIG. 4A and FIG. 4B.

FIG. 4A illustrates an osmotic delivery device (FIG. 4A, 400) comprisingtwo channels. A semi-permeable membrane 410 is adjacent an osmotic agentchamber 420 which is in fluid communication with two channels. In eachchannel, a piston assembly 430, 440 is placed to isolate the beneficialagent chamber 450, 460 from the osmotic agent chamber 420. At the distalend of channels is a diffusion moderator 470 that forms a flow path fromeach beneficial agent chamber to one or more orifice through which thebeneficial agent formulation will exit the device. The flow paths may,for example, (i) merge to a single flow path to a single orifice, (ii)flow into a cap-like structure as discussed herein above that results ina single exit orifice from the device (e.g., FIG. 3D), or (iii) eachdefine a flow path from a single beneficial agent chamber to an orifice(thus providing two orifices from which the beneficial agentformulations exit the device, one formulation from each orifice).

FIG. 4B illustrates the relationship of the two channels 450, 460 withina larger diameter columnar structure. FIG. 4B shows a cross sectionalarea at the dashed line of FIG. 4A. The two channels may, for example,be bored through solid columnar structure (e.g., made from a suitablereservoir material, such as titanium or a titanium alloy).

Advantages of this type of device include being a single implantabledevice useful for the delivery of, for example, multiple beneficialagent formulations in the same vehicle as well as multiple beneficialagent formulations in different vehicles, wherein the delivery rate ofthe beneficial agent formulations is determined based on a fluidimbibition rate of a single semi-permeable membrane and expansionproperty of a single osmotic agent formulation.

2.1.2.2 Grouped Devices

In another embodiment of the present invention, two or more osmoticdelivery devices each defining a single reservoir, for example, as shownin FIG. 1, are grouped together to form a single implantable device. Inthis embodiment, the individual osmotic delivery device reservoirs maybe attached by connecting means (e.g., biocompatible adhesives,elastomeric retaining rings, weld-joints, or tongue and grooveconnections).

The ends of the devices comprising the semi-permeable membrane aretypically adjacent as the diffusion moderator ends of the device arealso typically adjacent. Usually the ends of the devices are aligned;but the ends of the devices may also be staggered.

Devices of this type have the advantage of requiring only a singleimplantation while being useful for the delivery of, for example,multiple beneficial agent formulations in the same vehicle, multiplebeneficial agent formulations in different vehicles, as well as multiplebeneficial agent formulations for delivery at different rates.

2.1.2.3 Single Device, Two Beneficial Agent Chambers

Another embodiment of the present invention provides essentially for twoosmotic delivery systems within a single device. Examples of suchdevices include the following specific embodiments.

2.1.2.3.1 Concentric Devices

One embodiment of the present invention provides a single deliverydevice having a first beneficial agent reservoir within a secondbeneficial agent reservoir, wherein the first beneficial agent reservoirand the second beneficial agent reservoir are essentially concentric. Inthis embodiment, a first substantially columnar reservoir is providedwithin a second substantially columnar reservoir. The inner reservoirmay be stabilized within the outer reservoir by, for example, anessentially donut shaped semi-permeable membrane received in one end ofthe outer reservoir in sealing relationship with the inner surface ofthe outer reservoir, which also embraces the outer surface of the innerreservoir in sealing relationship. Similarly, the diffusion moderatormay stabilize the inner reservoir within the outer reservoir. Exactalignment of the components of the inner device is not required with thecomponents of the outer device, for example, the semi-permeable membraneof the inner device may be longer or shorter than the semi-permeablemembrane of the outer device, though of smaller diameter.

In this embodiment, each of the inner and outer devices has its owndiffusion moderator that defines a flow path from its respectivebeneficial agent chamber to an exit orifice. The flow path for the outerdevice may, for example, be formed by a channel created between theouter surface of the inner reservoir and the inner surface of thediffusion moderator.

Further, the exterior surface of the inner reservoir may be treated witha substance, such as a polymer or elastomer, that permits smoothoperation of the essentially donut-shaped piston over the outer surfaceof the second reservoir.

An example of this embodiment of an osmotic delivery device of thepresent invention 500 is illustrated in FIG. 5A to FIG. 5E. In FIG. 5Athe inner reservoir is shown in grey. The outer surface 505 of the innerreservoir provides the contact surface for the osmotic components of theouter reservoir. The outer surface of the outer reservoir 510 is theexterior surface of the device. A semi-permeable membrane 515 is insealing relationship with one end of the inner reservoir and asemi-permeable membrane 520 is in sealing relationship with one end ofthe outer reservoir. The semi-permeable membrane 520 may have adonut-like shape to provide a sealing relationship with the outersurface 505 of the inner reservoir as well as the inner surface of theouter reservoir. Further, a single component may comprise bothsemi-permeable membranes, for example, as a plug having a donut-likeouter portion, which provides a sealing relationship between the innersurface of the outer reservoir and the outer surface of the innerreservoir, and a nipple-like inner portion that provides a sealingrelationship with the inner surface of the inner reservoir.

Adjacent the semi-permeable membrane in both reservoirs are osmoticagent chambers 525, 530 formed between the semi-permeable membranes 515,520 and the piston assemblies 535, 540. Adjacent the pistons in bothreservoirs are beneficial agent chambers 545, 550 formed between thepistons 535, 540 and the diffusion moderators 555, 560.

FIG. 5B illustrates a cross-section of the semi-permeable membrane endof the device (FIG. 5A, 501). FIG. 5B shows the semi-permeable membranefor the inner reservoir 515, which is in sealing relationship with theinner surface of the inner reservoir, and the semi-permeable membranefor the outer reservoir 520, which is in sealing relationship with theouter surface of the inner reservoir 505 and the inner surface of theouter reservoir 510. As mentioned above, a single component may comprisethe two semi-permeable membranes. Alternately, each semi-permeablemembrane may be an individual component. Accordingly, the semi-permeablemembranes may be made of the same material or of different materials.

FIG. 5C illustrates an end view of the diffusion moderator end of thedevice (FIG. 5A, 502). Each beneficial agent chamber is in operativecontact with a flow path that leads to an exit orifice. The exit orifice565 for the beneficial agent chamber of the inner reservoir is typicallyadjacent the exit orifice 570 for the beneficial agent chamber of theouter reservoir. However, the exit orifice for the outer reservoir mayalso be, for example, located on the side of the device.

FIG. 5D illustrates an example of a donut-like diffusion moderator ofthe outer reservoir. The diffusion moderator of the outer reservoir 580has a donut-like shape that contacts in mating relationship the outersurface 505 of the inner reservoir and contacts in mating relationshipthe inner surface of the outer reservoir 512. In some embodiments theflow path between the beneficial agent chamber of the outer reservoir isformed in part by etching, grooving or engraving the flow path on theinner surface of the outer diffusion moderator 580 with the other partof the flow path formed by the outer surface 505 of the inner reservoir.In other embodiments the flow path is formed in part by etching,grooving or engraving the flow path on the outer surface 505 of theinner reservoir with the other part of the flow path formed by the innersurface of the outer diffusion moderator 580. An illustration of such aflow path 575 is shown in FIG. 5E. The two components shown in FIG. 5Eare normally in mating relationship but are shown separately toillustrate the flow path. The etched, grooved, or engraved flow pathcreates a functional channel when it is in mating relationship with theinterior surface of the exterior reservoir. The end of the flow channel585 is aligned with an exit orifice 570. In alternative embodiments, thediffusion moderator can, for example, (i) be press-fit (or friction fit)through an opening and contacting a smooth interior surface of thereservoir, or (ii) comprise two pieces with an outer shell constructedand arranged for positioning in an opening, an inner core inserted inthe outer shell, and a fluid channel having a spiral shape definedbetween the outer shell and the inner core (e.g., U.S. PatentPublication No. 2007-0281024).

In some embodiments, additional means are provided to hold the firstbeneficial agent reservoir within and in fixed-position relative to thesecond beneficial agent reservoir, for example, a cap-like structure atthe semipermeable membrane end comprising an opening to allowappropriate fluid imbibition, a cap-like structure at the diffusionmoderator end comprising one or more openings to allow appropriaterelease of the beneficial agent formulation, retaining means as part ofone or both of the semi-permeable membranes and/or diffusion modulators,structures at or near one or both ends of the device (e.g., single ormultiple supports connecting the inner surface of the outer reservoir tothe outer surface of the inner reservoir), structures at or near thesemipermeable membrane surface abutting the chamber containing theosmotic agent formulation (e.g., single or multiple supports connectingthe inner surface of the outer reservoir to the outer surface of theinner reservoir), and/or structures at or near the diffusion moderatorsurface abutting the chamber containing the beneficial agent formulation(e.g., single or multiple supports connecting the inner surface of theouter reservoir to the outer surface of the inner reservoir).

Devices of this type have the advantage of requiring only a singleimplantation while being useful for the delivery of, for example,multiple beneficial agent formulations in the same vehicle, multiplebeneficial agent formulations in different vehicles, as well as multiplebeneficial agent formulations for delivery at different rates.

2.1.2.3.2 Opposite End Orifices

In another embodiment of the present invention a device for dual osmoticdelivery is provided that has centrally located semi-permeable membranesfor fluid imbibition and distally located diffusion moderators forrelease of the beneficial agent formulations. Typically the devicecomprises a single, essentially columnar reservoir wherein an opening,or series of openings (e.g., a staggered ring of small holes drilledaround the circumference of the reservoir), is formed near the center ofthe reservoir. This opening, or series of openings, allows fluid to flowinto an interior chamber of the reservoir. This interior, fluidimbibition chamber of the reservoir is flanked on each side by asemi-permeable membrane held in sealing relationship with the interiorsurface of the reservoir. Adjacent each semi-permeable membrane is anosmotic agent chamber formed between the semi-permeable membranes andpiston assemblies located within the reservoir. Adjacent each pistonassembly is a beneficial agent chamber that is formed between the pistonassemblies and the diffusion moderators at each end of the device. Eachdiffusion moderator provides a flow path and an exit orifice for thebeneficial agent reservoir with which it is in fluid communication.

FIG. 6 presents a schematic illustration of an example of this type ofdevice 600. In FIG. 6, an opening for fluid imbibition 605 is centrallylocated in the reservoir, thus forming within the lumen of the reservoira chamber into which fluids from outside of the device may move into theinterior space of the device. Adjacent to the chamber for fluidimbibition are two semi-permeable membranes 610, 615 in sealingrelationship with the interior surface of the reservoir that create theends of the fluid imbibition chamber. Adjacent each semi-permeablemembrane an osmotic agent chamber 620, 625 is formed in the lumen of thereservoir between the semi-permeable membrane and the piston assemblies630, 635. Adjacent each piston assembly a beneficial agent chamber 640,645 is formed in the lumen of the reservoir between the piston assemblyand the diffusion moderators 650, 655. Each diffusion moderator createsa flow path between its adjacent beneficial agent chamber and an orifice660, 665 through which each beneficial agent formulation exits thedevice.

Another example of how this device can be configured with semi-permeablemembranes is that the device can comprise two reservoir components (FIG.6, 670, 675) that are held together in sealing, mating relationship witha centralized semi-permeable membrane. This centralized semi-permeablemembrane provides a path of fluid imbibition into each of the osmoticagent chambers 620, 625 and would replace the central chamber with anopening (FIG. 6, 605).

Devices of this type have the advantage of requiring only a singleimplantation while being useful for the delivery of, for example,multiple beneficial agent formulations in the same vehicle, multiplebeneficial agent formulations in different vehicles, as well as multiplebeneficial agent formulations for delivery at different rates.

2.1.2.3.3 Opposite End Semi-Permeable Membranes

In another embodiment of the present invention, a device for dualosmotic delivery is provided that has centrally located diffusionmoderators for release of the beneficial agent formulations and distallylocated semi-permeable membranes for fluid imbibition. Typically thedevice comprises a single, essentially columnar reservoir. Asemi-permeable membrane is provided at each end of the reservoir and isheld in sealing relationship with the interior surface of the reservoir.Adjacent each semi-permeable membrane is an osmotic agent chamber formedbetween the semi-permeable membranes and piston assemblies locatedwithin the reservoir. Adjacent each piston assembly is a beneficialagent chamber that is formed between the piston assemblies and thediffusion moderators centrally located within the device. Each diffusionmoderator provides a flow path and an exit orifice for the beneficialagent reservoir with which it is in fluid communication.

FIG. 7A presents a schematic illustration of an example of this type ofdevice 700. At each end of the reservoir a semi-permeable membrane 705,710 is provided in sealing relationship with the interior wall ofreservoir. Adjacent each semi-permeable membrane an osmotic agentchamber 715, 720 is formed between the semi-permeable membrane 705, 710and the piston assembly 725, 730. Adjacent each piston assembly 725,730, a beneficial agent chamber 735, 740 is formed between the pistonassembly 725, 730 and the diffusion moderator 750. The diffusionmoderator defines a flow path and an exit orifice 751, 752 for eachbeneficial agent chamber.

The diffusion moderator may, for example, be a single component asillustrated in FIG. 7B. The flow paths may, for example, be etched,grooved, or engraved on the exterior surface of the diffusion moderatorsuch that a flow path 755 (terminating at 753), 760 (terminating at 754)from each beneficial agent chamber 735, 740 to an associated exitorifice 751, 752 is created, for example, the termination point 753 isaligned with exit orifice 751 and termination point 754 is aligned withexit orifice 752, thus providing a flow path for liquid from within eachbeneficial agent chamber to the exterior of the device. The exitorifices may be formed, for example, by boring holes in the reservoir.

In alternative embodiments, the diffusion moderator can, for example,(i) be press-fit (or friction fit) and contact a smooth interior surfaceof the reservoir, or (ii) comprise two pieces with an outer shellconstructed and arranged for positioning in an opening, an inner coreinserted in the outer shell, and fluid channels defined between theouter shell and the inner core (e.g., U.S. Patent Publication No.2007-0281024).

Alternately, a diffusion moderator may be located at the end of eachbeneficial agent chamber and a diffusion chamber created between the twodiffusion moderators. The flow paths defined by the two diffusionmoderators may provide an avenue of fluid communication between eachbeneficial agent chamber and the diffusion chamber. In this case, one ormore exit orifice from the device can be provided for the beneficialagent formulations to exit from the diffusion chamber of the device.

Another example of how this device can be configured with diffusionmoderators is that the device can comprise two reservoir components(FIG. 7A, 775, 780) that are held together in mating relationship with acentralized diffusion moderator. This centralized diffusion moderatorprovides a flow path that connects each beneficial agent chamber to anexit orifice, that is, each beneficial agent chamber has a flow path toan associated orifice similar to the diffusion moderator shown in FIG.7B.

Devices of this type have the advantage of requiring only a singleimplantation while being useful for the delivery of, for example,multiple beneficial agent formulations in the same vehicle, multiplebeneficial agent formulations in different vehicles, as well as multiplebeneficial agent formulations for delivery at different rates.

2.1.3 Examples of Component Materials

The following materials are examples of materials that can be used tomake the components of the above-described devices.

The pistons of the present invention are typically columnar in shape andmay be solid or hollow (e.g., donut-like) depending on the type ofdevice. The columnar body is preferably made of a polymeric materialthat is substantially impermeable to and substantially resistant toleaching when exposed to any solvent, for example, an organic solvent,used in the beneficial agent formulation. Examples of polymericmaterials suitable for making the body of the piston assembly include,but are not limited to, the following: polyethylene (e.g., ultra-highmolecular weight polyethylene (UHMWPE)); polyaryletherketones (e.g.,polyetherketone and polyetheretherketone (PEEK)); andultra-high-molecular-weight polyethylene. Other examples of usefulpolymers include, but are not limited to, the following: perfluoronatedelastomers and polymers (e.g., elastomeric materials having broadchemical resistance, combining the resilience and sealing force of anelastomer with chemical resistance approaching that ofpolytetrafluoroethylene (PTFE) as available, for example, CHEMRAZ™(Greene, Tweed of Delaware, Inc., Wilmington, Del.) materials);polyimides; and polysulfones. In a preferred embodiment the polymericmaterial has some natural lubricity relative to the material comprisingthe inner wall of the lumen. The polymeric material may be one thatadheres to the wall of the reservoir upon wetting. Piston assemblies maybe a single component or a collection of components. For example, asubstantially rigid piston may be formed wherein the surface of thepiston is scored to provide a groove for the placement of an O-ring toprovide an additional sealing component for contact with the interiorsurface of the reservoir.

In addition to use of a solid core of the polymeric materials to makethe piston assembly, a thick impermeable coating of one or more solventresistant polymer on a dissimilar core substrate may be used.Elastomers, for example, perfluoroelastomer, typically have broadchemical resistance. As an alternative to the elastomers coating anentire piston core, a thin, perfluoroelastomer O-ring, gasket, orcoating may be installed on to or applied to on a rigid core material(e.g., thermoplastic, ceramic, metal) to create an acceptable pistonseal. In addition a metal spring (e.g., a canted coil spring) may beused to apply a force to a portion of the surface of the piston againstthe inner wall of the reservoir to create an acceptable seal.

Furthermore, although an exemplary shape of the piston is described as acylinder, the shape of the piston assembly may vary from a cylindricalshape (e.g., the piston may have an hour glass shape that contacts withthe inner surface of the lumen near the distal ends). Shape of thepiston assembly is typically such that it contacts the inner surface ofthe lumen to (i) provide separation between the beneficial agent chamberand the osmotic agent chamber of the lumen, and (ii) preventflow-through there between. In preferred embodiments, the pistonassembly substantially prevents fluid exchange between the beneficialagent chamber and the osmotic agent chamber of the lumen.

Semi-permeable materials suitable for the semi-permeable membrane arethose that can conform to the shape of the lumen of the reservoir uponwetting. Preferably, these materials can also adhere to the wall of thereservoir upon wetting, thereby providing or maintaining a seal betweenthe wall and the semi-permeable membrane. Typically, thesesemi-permeable materials are polymeric materials, which can be selectedbased on the permeability of the membrane and system configurationrequirements. Examples of suitable semi-permeable materials include, butare not limited to, plasticized cellulosic materials; enhancedpolymethyl methacrylates (PMMAs) such as hydroxyethylmethacrylate(HEMA); and elastomeric materials such as polyurethanes,polyetherurethane, polyetherurethane copolymers and polyamides,polyether-polyamind copolymers, thermoplastic copolyesters; and thelike. Semi-permeable membranes are typically formed as plugs thatprovide a sealing relationship with the interior surface of eachreservoir in which they come in contact.

Generally the membrane permeability ranges of the polymeric material isselected in order to provide the appropriate influx of aqueous solutioninto the lumen of the osmotic delivery device such that the osmoticagent expands at a rate determined to provide delivery of a beneficialagent at a desired rate for a selected period of time. In one embodimentof the present invention, the semi-permeable membrane is an aliphatic,polyether-based polyurethane. The thermoplastic polyurethane may beinjection molded to form a membrane with barbed, concentric ribs and anenlarged portion that acts as a stop member. Semipermeable membranes foruse in the present invention are typically plug-shaped and may, forexample, have a treaded surface or annular ribs to sealingly engagegrooves on the interior surface of a reservoir, have a treaded surfaceor annular ribs to sealingly engage a smooth interior surface of areservoir, be adapted to press-fit (or friction fit) through an openingand contact a smooth interior surface of the reservoir, and so on.Examples of semipermeable membranes useful in the practice of thepresent invention have been described (e.g., U.S. Pat. Nos. 6,113,938,6,270,787, 6,287,295, 6,375,978, 7,163,688; U.S. Published PatentApplication Nos. 2005-0010196, 2005-0101943).

The osmotic agent (or water-swellable agent) formulation (e.g., in theosmotic agent chamber) is preferably a tissue tolerable formulationwhose high osmotic pressure and high solubility propels the beneficialagent over a long period of time while remaining in saturated solutionin the water admitted by the semi-permeable membrane. The osmotic agentis preferably selected for tolerability by subcutaneous tissue, at leastat pumping rates and hypothetically resulting concentrations to allowinadvertent dispensing from implanted devices left in the patient for alonger than the labeled period. In preferred embodiments, the osmoticagent does not diffuse or permeate through the piston assembly to anyappreciable amount (e.g., less than about 10%, more preferably less thanabout 8%, more preferably less than about 6%) under normal operatingconditions.

The osmotic agent formulation may be, for example, in the form oftablets. One or more such tablets may be used. Alternatively, theosmotic agent formulation may have other shape, texture, density, and/orconsistency. For example, the osmotic agent formulation may be a slurry,a tablet, a molded or extruded material, a powder or granular form, orother form known in the art. The osmotic agent formulation may includeone or more osmotic polymers. An osmotic polymer is a hydrophilicpolymer that can imbibe aqueous fluids (such as biological fluids andwater) and upon imbibing aqueous fluids expands to an equilibrium stateand retains a significant portion of the imbibed fluid. An osmoticpolymer can expand to a very high degree, for example, about 2 to about50 times its initial volume. An osmotic polymer may or may not becross-linked. Preferred osmotic polymers are hydrophilic polymers thatare lightly cross-linked, such cross-links being formed by covalent orionic bonds or residue crystalline regions after swelling. Osmoticpolymers may be, for example, of plant, animal or synthetic origin.

Examples of osmotic polymers suitable for use in the osmotic agentformulation include, but are not limited to, poly (hydroxy-alkylmethacrylate) having a molecular weight of from 30,000 to 5,000,000;polyvinylpyrrolidone (PVP) having a molecular weight of from 10,000 to360,000; anionic and cationic hydrogels; polyelectrolytes complexes;polyvinyl alcohol having a low acetate residual, cross-linked withglyoxal, formaldehyde, or glutaraldehyde and having a degree ofpolymerization of from 200 to 30,000; a mixture of methyl cellulose,cross-linked agar and carboxymethyl cellulose; a mixture ofhydroxypropyl methylcellulose and sodium carboxymethylcellulose; amixture of hydroxypropyl ethylcellulose and sodium carboxymethylcellulose; sodium carboxymethylcellulose; potassiumcarboxymethylcellulose; a water insoluble, water swellable copolymerformed from a dispersion of finely divided copolymer of maleic anhydridewith styrene, ethylene, propylene, butylene or isobutylene cross-linkedwith from 0.001 to about 0.5 moles of saturated cross-linking agent permole of maleic anhydride per copolymer; water swellable polymers ofN-vinyl lactams; polyoxyethylene-polyoxypropylene gel;polyoxybutylene-polyethylene block copolymer gel; carob gum; polyacrylicgel; polyester gel; polyuria gel; polyether gel; polyamide gel;polypeptide gels; polyamino acid gels; polycellulosic gel; polygum gel;and initially dry hydrogels that imbibe and absorb water that penetratesthe glassy hydrogel and lowers its glass temperature.

Other examples of osmotic polymers include, but are not limited to, thefollowing: polymers that form hydrogels such as CARBOPOL™ (Noveon, Inc.,Cleveland, Ohio), acidic carboxypolymer, a polymer of acrylic andcross-linked with a polyallyl sucrose, also known ascarboxypolymethylene and carboxyvinyl polymer having a molecular weightof 250,000 to 4,000,000; cynamer polyacrylamides; cross-linked waterswellable indene-maleic anhydride polymers; GOOD-RITE™ (Noveon, Inc.,Cleveland, Ohio) polyacrylic acid having a molecular weight of 80,000 to200,000; POLYOX™ (Union Carbide Chemicals & Plastics TechnologyCorporation, Danbury, Conn.) polyethylene oxide polymer having amolecular weight of 100,000 to 5,000,000 and higher; starch graftcopolymers; acrylate polymer polysaccharides composed of condensedglucose units such as diester cross-linked polygluran; and the like.

The osmotic agent formulation may include an osmotic effective soluteeither in addition to or in lieu of the osmotic polymer described above.Osmotic effective solutes include inorganic and organic compounds thatcan exhibit an osmotic pressure gradient across the semi-permeablemembrane when the osmotic delivery system is placed in a fluidenvironment. An osmotic effective solute in the osmotic agentformulation imbibes fluid into the osmotic agent chamber through thesemi-permeable membrane, thereby making available fluid pressure todisplace the piston assembly and push the beneficial agent formulationthrough the delivery (or exit) orifice via the diffusion moderator.Osmotic effective solutes or osmagents (i.e., the non-volatile speciesthat are soluble in water and create the osmotic gradient driving theosmotic inflow of water) useful in the osmotic agent formulationinclude, but are not limited to, magnesium sulfate, magnesium chloride,sodium chloride, potassium sulfate, sodium sulfate, lithium sulfate,sodium phosphate, potassium phosphate, d-mannitol, urea, inositol,magnesium succinate, tartaric acid, inositol, carbohydrates, and variousmonosaccharides, oligosaccharides and polysaccharides such as sucrose,glucose, lactose, fructose, raffinose and dextran, as well as mixturesof any of these various species.

Osmotic agents such as sodium chloride (NaCl) with appropriatetabletting agents (lubricants and binders; e.g., cellulosic and povidonebinders) and viscosity modifying agents, such as sodiumcarboxymethylcellulose or sodium polyacrylate are examples of preferredosmotic agents. Other osmotic agents useful as the water-swellable agentinclude osmopolymers and osmagents and are described, for example, inU.S. Pat. No. 5,413,572. A liquid or gel additive or filler may be addedto the chamber containing the osmotic agent formulation to exclude airspaces. Exclusion of air from the devices generally means that deliveryrates will be less affected by nominal external pressure changes.

Materials that may be used for the reservoir are sufficiently rigid towithstand expansion of the osmotic agent formulation without changingits size or shape. Where the osmotic delivery system is implantable, thematerials are typically selected to ensure that the reservoir will notleak, crack, break, or distort under stresses to which it may besubjected during implantation or under stresses due to the pressuresgenerated during operation. The reservoir may be formed of non-reactive(or inert), biocompatible, natural or synthetic materials that are knownin the art. Preferably, the material of the reservoir isnon-bioerodible. Generally, preferred materials for the reservoir arethose acceptable for human implantation. Preferably, the material of thereservoir is impermeable, particularly when stability of the formulationin the reservoir is sensitive to fluids in the fluid environment of use(e.g., after implantation in a subject).

Examples of materials suitable for the reservoir include non-reactive,biocompatible polymers and metals or alloys. Examples of non-reactive,biocompatible polymers for the reservoir include, but are not limitedto, acrylonitrile polymers such as acrylonitrile-butadiene-styreneterpolymer; halogenated polymers such as polytetrafluoroethylene,polychlorotrifluoroethylene, copolymer tetrafluoroethylene andhexafluoropropylene; polyimide; polysulfone; polycarbonate;polyethylene; polypropylene; polyvinylchloride-acrylic copolymer;polycarbonate-acrylonitrile-butadiene-styrene; and polystyrene. Examplesof metallic, biocompatible materials for the reservoir include, but arenot limited to, stainless steel, titanium, platinum, tantalum, gold, andtheir alloys, as well as gold-plated ferrous alloys, platinum-platedferrous alloys, cobalt-chromium alloys and titanium nitride coatedstainless steel. For size-critical applications, high payloadcapabilities, long duration applications, and applications where theformulation is sensitive to body chemistry at the implantation site, thereservoir is preferably made of titanium or a titanium alloy havinggreater than about 60%, more preferably greater than about 85% titanium.

The total size of the reservoir is selected based on a variety ofparameters, for example, (i) the volume occupied by a diffusionmoderator, (ii) the volume occupied by an beneficial agent formulation,(iii) the volume occupied by a piston assembly, (iv) the volume occupiedby an osmotic agent formulation, (v) the volume occupied by asemi-permeable membrane, and (vi) the number of beneficial agentchambers.

The diffusion moderator is typically a plug-like member defining aliquid flow path for exit of the beneficial agent formulation from theosmotic delivery system (e.g., U.S. Pat. Nos. 5,728,396, 5,997,527,6,217,906, 6,287,295, 6,395,292, 6,524,305, 6,635,268, 6,840,931, and6,923,800; U.S. Patent Application Publication No. 2005-0175701,2007-0281024).

The present invention is not limited to any particular diffusionmoderator as long as the diffusion moderator is able to deliver thebeneficial agent formulation in a desired manner. Preferably, thediffusion moderator allows delivery of the beneficial agent formulationwhile controlling back-diffusion of external fluid into the lumen of thereservoir. The distal end may be open and the diffusion moderator may beprovided in the form of a plug that is inserted in the open end.Alternately, the diffusion moderator may be integrated with a distal endof the reservoir.

The delivery orifice flow channel provided by the diffusion moderatormay be, for example, spiral in shape or straight. Further, the orificeflow channel may be of a variety of shapes including, but not limitedto, circular, triangular, square, D-shaped, oval, or elongated (e.g.,slit-like). The diffusion moderator is preferably made of a non-reactive(or inert), biocompatible material. Exemplary materials include, but arenot limited to, metals such as titanium, stainless steel, platinum andtheir alloys, and cobalt-chromium alloys. Other compatible materialsinclude polymers such as polyethylene, polypropylene, polycarbonate,polymethylmethacrylate, and polyaryletherketones, e.g.,polyetheretherketone (PEEK). Typically, the flow channel has a nominal“diameter” (i.e., measured across the widest opening) of between about0.05 mm to about 0.75 mm, preferably between about 0.15 mm to about 0.50mm. In one embodiment, the orifice flow channel is a D-shaped channelhaving a nominal “diameter” of about 250 μm (about 0.25 mm).

The diffusion moderator may be assembled to the reservoir by using anumber of methods, for example, a thread and screw method wherein thediffusion moderator or the interior surface of the lumen or bothcomprise ribs, for example, complementary continuous helicalthreads/grooves. Single, double, triple, or quadruple threads/groovesmay be used.

Alternatively, the diffusion moderator may be assembled to the reservoirby a press-fit (i.e., interference fit) where the outside of thediffusion moderator is slightly larger than the inside diameter of thereservoir. Typically, this assembly method is faster and easier toautomate than other assembly methods that may be used in the practice ofthe present invention such as thread and screw assemblies.

An osmotic delivery system diffusion moderator assembly may alsoinclude, for example, a body defining an open pathway (e.g., a hole orflow channel) through the body of the diffusion moderator thatcommunicates between two opposing ends of the body (e.g., where theorifice defines the exit site of the beneficial agent). The open pathwaymay be, for example, straight, spiral, or curved. The diffusionmoderator may further comprise a stopper that serves to close theorifice to the external environment until the osmotic delivery system isready for use (e.g., U.S. Pat. No. 6,524,305). Prior to use, such astopper is removed.

In one embodiment, the diffusion moderator comprises two parts (e.g.,two polyetheretherketone machined parts as described in U.S. PatentPublication No. 2007-0281024), an inner core and an outer sleeve,whereby a continuous spiral delivery channel is formed between the twoparts when they are assembled. The two-piece moderator is assembled bypress-fitting into the reservoir (wherein neither the reservoir nor themoderator comprises ribs). In other embodiments, ribbed components maybe used. Such two-piece diffusion moderators can be adapted for use inall embodiments of osmotic delivery devices described herein.

Delivery rates of beneficial agent formulations from the osmoticdelivery devices of the present invention may be varied by, for example,using different diffusion moderator flow path sizes (e.g., length orwidth), different semi-permeable membranes associated with separateosmotic agent chambers, different osmotic agents within differentosmotic agent chambers wherein, for example, the osmotic agents havedifferent expansion properties.

The present invention also includes methods of manufacturing the osmoticdelivery systems of the present invention. Typically a method ofmanufacturing comprises providing the device components and positioningthe components in appropriate functional relationship with each other,as described herein, to make the osmotic delivery device. Such methodsalso typically comprise filling the appropriate chambers with one ormore osmotic agent formulation and filling the appropriate chambers withone or more beneficial agent formulation.

Furthermore, the osmotic delivery systems of the present invention maybe individually packaged or packaged in groups. Such packaging may be,for example, foil pouches or vials. The packaging may include adesiccant or the osmotic delivery systems may be packaged under nitrogenor vacuum.

Examples of beneficial agents and beneficial agent formulations for usein the practice of the present invention are discussed further hereinbelow and these beneficial agents may be used singly in formulations orin the described combined formulations. Accordingly, an osmotic deliverydevice having two beneficial agent chambers can be used, for example, toadminister two beneficial agents, wherein each beneficial agent isprepared in a separate formulation, or to deliver more than twobeneficial agents, wherein two or more beneficial agents are formulatedtogether for delivery from at least one of the beneficial agentchambers.

2.1.4 Advantages of the Devices of the Present Invention

The devices of the present invention that provide multiple beneficialagent chambers provide many advantages for the administration ofbeneficial agent formulations including, but not limited to, thefollowing. First, within a single device a beneficial agent may bedelivered for a short period of time (e.g., weeks or months), forexample, to begin therapy, and a second beneficial agent may bedelivered for a longer period of time (e.g., weeks, months, or even ayear or more). Alternatively, the same beneficial agent may be providedat a different dosage in one beneficial agent chamber relative toanother beneficial agent chamber to provide step-down or step-upadministration of the beneficial agent.

An example of step-down administration is if beneficial agentformulation A is delivered at amount X from beneficial agent chamber 1,and the same beneficial agent formulation A is delivered at amount Xfrom beneficial agent chamber 2 but a smaller volume of the beneficialagent formulation is provided in chamber 1 so that when the beneficialagent formulation from chamber 1 is depleted the amount of beneficialagent being delivered goes from 2X to X. In this example, delivery ofthe beneficial agent from both chambers begins concurrently.

An example of step-up administration is if beneficial agent formulationA is delivered at amount X from a first beneficial agent chamber A, andthe same beneficial agent is delivered in formulation B at amount 2Xfrom a second beneficial agent chamber B but beneficial agent chamber Ahas a smaller volume of the beneficial agent formulation and isassociated with a semi-permeable membrane that is selected to imbibewater at a faster rate to deliver the volume from beneficial agentchamber A corresponding to the desired low dose period. The volume ofbeneficial agent chamber B is the same or larger and is associated witha semi-permeable membrane that imbibes water at a slower rate providinga longer duration of dosing. Beneficial agent chamber B is partiallyfilled with a viscous formulation of beneficial agent comprising aconcentration of the beneficial agent to deliver 2X. The remainder ofthe beneficial agent chamber B is filled with a layer of vehicle notcontaining the beneficial agent, the volume of this layer of vehicle andrate of water imbibed by the semi-permeable membrane are selected tocorrespond with the duration of dosing for beneficial agent chamber A.As beneficial agent is delivered from beneficial agent chamber A, onlyvehicle is being delivered from beneficial agent chamber B and whenbeneficial agent chamber A is depleted the beneficial agent is deliveredfrom beneficial agent chamber B at a rate of 2X.

A second advantage of the devices of the present invention can be seenfrom the previous description wherein delivery of a first beneficialagent from the first beneficial agent chamber is of different durationthan delivery of a second beneficial agent from the second beneficialagent chamber.

A third advantage of the devices of the present invention is thatdelivery of a first beneficial agent from the first beneficial agentchamber is at a different rate than delivery of a second beneficialagent from the second beneficial agent chamber.

A fourth advantage of the devices of the present invention is that theycan provide, from a single device, delivery of multiple beneficialagents from the same device when the beneficial agents cannot beformulated together, for example, because of drug incompatibility ordifferent vehicle requirements (e.g., solubility differences of thebeneficial agents in solvents/polymers). Multiple beneficial agentchambers offer formulation flexibility because, for example, differentsolvents, vehicles, particles, and strength combinations can be used inseparate beneficial agent chambers.

A fifth advantage of the devices of the present invention is to provideco-administration of two or more beneficial agents from a single device.Examples of co-administration of specific beneficial agents aredescribed herein below.

Such implantable osmotic delivery devices can be designed to providetherapeutic doses of the drug over periods of weeks, months, or even ayear or more. Implantable osmotic delivery systems, once inserted in asubject, administer therapeutic doses without relying on or requiringany action of the subject. Accordingly, compliance to a required dosingregimen is generally ensured.

2.2 Beneficial Agent Formulations

The beneficial agent formulation, which occupies a beneficial agentchamber of an osmotic delivery device, may comprise one or morebeneficial agents. The beneficial agent may be any physiologically orpharmacologically active substance, particularly those known to bedelivered to the body of a human or an animal such as medicaments,vitamins, nutrients, or the like. Beneficial agents that may bedelivered by the osmotic delivery system of the present inventioninclude, but are not limited to, drugs that act on the peripheralnerves, adrenergic receptors, cholinergic receptors, the skeletalmuscles, the cardiovascular system, smooth muscles, the bloodcirculatory system, synoptic sites, neuroeffector junctional sites,endocrine and hormone systems, the immunological system, thereproductive system, the skeletal system, autacoid systems, thealimentary and excretory systems, the histamine system or the centralnervous system. Further, beneficial agents that may be delivered by theosmotic delivery system of the present invention include, but are notlimited to, beneficial agents used for the treatment of infectiousdiseases, chronic pain, diabetes, auto-immune disorders, endocrinedisorders, metabolic disorders, oncological diseases, and rheumatologicdisorders, central nervous system (CNS) related disorders, andpsychiatric disorders.

2.2.1 Examples of Beneficial Agents

Suitable beneficial agents include, but are not limited to, thefollowing: peptides, proteins, polypeptides (e.g., enzymes, hormones,cytokines), polynucleotides, nucleoproteins, polysaccharides,glycoproteins, lipoproteins, steroids, analgesics, local anesthetics,antibiotic agents, anti-inflammatory corticosteroids, ocular drugs,other small molecules for pharmaceutical use, or synthetic analogs ofthese species, as well as mixtures thereof. Preferred beneficial agentsinclude macromolecules (e.g., peptides, proteins and polypeptides) orbeneficial agents that are highly potent.

The osmotic devices of the invention may be used to deliver a widevariety of beneficial agents. These agents include, but are not limitedto, pharmacologically beneficial peptides proteins, polypeptides, genes,gene products, other gene therapy agents, or other small molecules. Thepolypeptides may include but are not limited to the following: growthhormone; somatostatin; somatropin, somatotropin, somatotropin analogues,somatomedin-C, somatotropin plus an amino acid, somatotropin plus aprotein; follicle stimulating hormone; luteinizing hormone, luteinizinghormone-releasing hormone (LHRH), LHRH analogues/agonists such asleuprolide, nafarelin and goserelin, LHRH antagonists; growth hormonereleasing factor; calcitonin; colchicine; gonadotropins such aschorionic gonadotropin; antiandrogens such as flutamide, nilutamide andcytoprerone; aromatase inhibitors such as exemastane, letrozole andanastrazole; selective estrogen receptive modulators such as raloxifene,lasoxifene; oxytocin, octreotide; vasopressin; adrenocorticotrophichormone; epidermal growth factor; fibroblast growth factor;platelet-derived growth factor; transforming growth factor; nerve growthfactor; prolactin; cosyntropin; lypressin polypeptides such asthyrotropin releasing hormone; thyroid stimulation hormone; secretin;leptin; amylin, amylin analogues (e.g., pramlintide acetate);pancreozymin; enkephalin; glucagon; endocrine agents secreted internallyand distributed by way of the bloodstream; or the like.

Further beneficial agents that may be delivered include but are notlimited to the following: alpha antitrypsin; factor VII; factor IX,thrombin and other coagulation factors; insulin; peptide hormones;adrenal cortical stimulating hormone, thyroid stimulating hormone andother pituitary hormones; erythropoietin; growth factors such asgranulocyte-colony stimulating factor, granulocyte-macrophage colonystimulating factor, thrombopoietin, insulin-like growth factor 1; tissueplasminogen activator; CD4; 1-deamino-8-D-arginine vasopressin;interleukin-1 receptor antagonist; tumor necrosis factor, tumor necrosisfactor receptor; tumor suppresser proteins; pancreatic enzymes; lactase;cytokines, including lymphokines, chemokines or interleukins such asinterleukin-1, interleukin-2 and other members of the interleukin family(e.g., IL-1, 6, 12, 15, 17, 18, 32); cytotaxic proteins; superoxidedismutase; endocrine agents secreted internally and distributed in ananimal by way of the bloodstream; recombinant antibodies, antibodyfragments, humanized antibodies, single chain antibodies, monoclonalantibodies; avimers; or the like.

Further, the beneficial agents that may be administered include, but arenot limited to, organic compounds including those compounds thattransport across a vessel. Examples of beneficial agents that may beused in the practice of the present invention include, but are notlimited to, the following: hypnotics and sedatives such as pentobarbitalsodium, phenobarbital, secobarbital, thiopental, amides and ureasexemplified by diethylisovaleramide and alpha-bromo-isovaleryl urea,urethanes, or disulfanes; heterocyclic hypnotics such asdioxopiperidines, and glutarimides; antidepressants such asisocarboxazid, nialamide, phenelzine, imipramine, tranylcypromine,pargyline; tranquilizers such as chloropromazine, promazine,fluphenazine reserpine, deserpidine, meprobamate, benzodiazepines suchas chlordiazepoxide; tricyclic antidepressants; anticonvulsants such asprimidone, diphenylhydantoin, ethltoin, pheneturide, ethosuximide;muscle relaxants and anti-parkinson agents such as mephenesin,methocarbomal, trihexylphenidyl, biperiden, levo-dopa, also known asL-dopa and L-beta-3-4-dihydroxyphenylalanine; analgesics such asmorphine, codeine, meperidine, nalorphine; antipyretics andanti-inflammatory agents such as aspirin, salicylamide, sodiumsalicylamide, naproxin, ibuprofen, acetaminophen; local anesthetics suchas procaine, lidocaine, naepaine, piperocaine, tetracaine, dibucane;antispasmodics and antiulcer agents such as atropine, scopolamine,methscopolamine, oxyphenonium, papaverine, prostaglandins such as PGE₁,PGE₂, PGF_(1alpha), PGF_(2alpha), PGA; anti-microbials such aspenicillin, tetracycline, oxytetracycline, chlorotetracycline,chloramphenicol, sulfonamides, bacitracin, chlorotetracycline,levofloxacin, erythromycin; anti-fungals such as Amphotericin B;anti-malarials such as 4-aminoquinolines, 8-aminoquinolines andpyrimethamine; hormonal agents such as prednisolone, cortisone, cortisoland triamcinolone, androgenic steroids (for example, methyltestosterone,fluoxmesterone), estrogenic steroids (for example, 17-beta-estradoil andthinyl estradiol), progestational steroids (for example,17-alpha-hydroxyprogesterone acetate, 19-nor-progesterone,norethindrone); sympathomimetic drugs such as epinephrine, amphetamine,ephedrine, norepinephrine; cardiovascular drugs such as procainamide,amyl nitrate, nitroglycerin, dipyridamole, sodium nitrate, mannitolnitrate; diuretics such as acetazolamide, chlorothiazide, flumethiazide;antiparasitic agents such as bephenium hydroxynaphthoate, dichlorophen,enitabas, dapsone; anti-neoplastic agents such as mechloroethamine,uracil mustard, 5-fluorouracil, 6-thioguanine, procarbazine, paclitaxel,docetaxel, carboplatin, gemcitabine, oxaliplatin, fludarabine, ara-C,camptothecin, bortezomib, methrotrexate, capecitabine, doxorubicin,vincristine, cyclophosphamide, etoposide; VEGF/EGF inhibitors (forexample, small molecules and antibodies); hypoglycemic drugs such asinsulin related compounds (for example, isophane insulin suspension,protamine zinc insulin suspension, globin zinc insulin, extended insulinzinc suspension) tolbutamide, acetohexamide, tolazamide, chlorpropamide;nutritional agents such as vitamins, essential amino acids, andessential fats; eye drugs such as pilocarpine base, pilocarpinehydrochloride, pilocarpine nitrate; antiviral drugs such as disoproxilfumarate, aciclovir, cidofovir, docosanol, famciclovir, fomivirsen,foscarnet, ganciclovir, idoxuridine, penciclovir, trifluridine,tromantadine, valaciclovir, valganciclovir, vidarabine, amantadine,arbidol, oseltamivir, peramivir, rimantadine, zanamivir, abacavir,didanosine, emtricitabine, lamivudine, stavudine, zalcitabine,zidovudine, tenofovir, efavirenz, delavirdine, nevirapine, loviride,amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir,nelfinavir, ritonavir, saquinavir, tipranavir, enfuvirtide, adefovir,fomivirsen, imiquimod, inosine, podophyllotoxin, ribavirin, viramidine,fusion inhibitors specifically targeting viral surface proteins or viralreceptors (for example, gp-41 inhibitor (T-20), CCR-5 inhibitor, FUZEON™(Trimeris, Inc., Morrisville, N.C.; enfuvirtide)); anti-nausea (such asscopolamine, dimenhydrinate, metaclopramide, ondansetron); iodoxuridine,hydrocortisone, eserine, phospholine, iodide, as well as otherbeneficial beneficial agents.

Examples of beneficial agent formulations comprising a small molecule(e.g., Amphotericin B) are given in Examples 6A and 6B.

Numerous peptides, proteins, or polypeptides that are useful in thepractice of the present invention are described herein. In addition tothe peptides, proteins, or polypeptides described, modifications ofthese peptides, proteins, or polypeptides are also known to one of skillin the art and can be used in the practice of the present inventionfollowing the guidance presented herein. Such modifications include, butare not limited to, amino acid analogs, amino acid mimetics, analogpolypeptides, or derivative polypeptides. Further, the beneficial agentsdisclosed herein may be formulated singly or in combination (e.g.,mixtures).

Further, oligonucleotides (e.g., RNA, DNA, alternative backbones) may beused as beneficial agents in the practice of the present invention. Inone embodiment therapeutic RNA molecules may include, but are notlimited to, small nuclear RNAs (snRNAs), and small interfering RNAstrands (siRNA) for use in RNA interference (RNAi) inhibition of geneexpression. RNAi inhibition typically occurs at the stage of translationor by hindering the transcription of specific genes. RNAi targetsinclude, but are not limited to, RNA from viruses and genes with rolesin regulating development and genome maintenance.

Some embodiments of the present invention comprise use of interferon forthe treatment of interferon responsive diseases or disorders. An exampleof an interferon particle formulation is given in Example 5.

Some embodiments of the present invention comprise the use of peptidehormones for the treatment of diabetes and diabetes related conditions(e.g., insulinotropic peptides such as glucagon like protein (such asGLP-1), as well as analogues and derivatives thereof, or exendins (suchas exendin-4), as well as analogs and derivatives thereof).

Numerous GLP-1 derivatives and analogues demonstrating insulinotropicaction are known in the art (e.g., U.S. Pat. Nos. 5,118,666, 5,120,712,5,512,549, 5,545,618, 5,574,008, 5,574,008, 5,614,492, 5,958,909,6,191,102, 6,268,343, 6,329,336, 6,451,974, 6,458,924, 6,514,500,6,593,295, 6,703,359, 6,706,689, 6,720,407, 6,821,949, 6,849,708,6,849,714, 6,887,470, 6,887,849, 6,903,186, 7,022,674, 7,041,646,7,084,243, 7,101,843, 7,138,486, 7,141,547, 7,144,863, and 7,199,217).Accordingly, for ease of reference herein, the family of GLP-1derivatives and analogues having insulinotropic activity is referred tocollectively as GLP-1.

The exendins are peptides that were isolated from the venom of theGila-monster. Exendin-4 is present in the venom of Heloderma suspectum(Eng, J., et al., J. Biol. Chem., 265:20259-62 (1990); Eng., J., et al.,J. Biol. Chem., 267:7402-05 (1992); U.S. Pat. No. 5,424,286). Based ontheir insulinotropic activities, use of exendin-3 and exendin-4 for thetreatment of diabetes mellitus and the prevention of hyperglycemia hasbeen proposed (e.g., U.S. Pat. No. 5,424,286). Numerous exendin-4derivatives, and analogues (including, e.g., exendin-4 agonists)demonstrating insulinotropic action are known in the art (e.g., U.S.Pat. Nos. 5,424,286, 6,268,343, 6,329,336, 6,506,724, 6,514,500,6,528,486, 6,593,295, 6,703,359, 6,706,689, 6,767,887, 6,821,949,6,849,714, 6,858,576, 6,872,700, 6,887,470, 6,887,849, 6,924,264,6,956,026, 6,989,366, 7,022,674, 7,041,646, 7,115,569, 7,138,375,7,141,547, 7,153,825, and 7,157,555). Exenatide is a synthetic versionof exendin-4 (Kolterman O. G., et al., J. Clin. Endocrinol. Metab.88(7):3082-9 (2003)). Accordingly, for ease of reference herein, thefamily of exendin-4 polypeptides, exendin-4 derivatives, variants andanalogues having insulinotropic activity is referred to collectively asexendin-4. Examples of exendin-4 particle formulations are given inExamples 1, 4A, and 4B.

Peptide YY (PYY) inhibits gut motility and blood flow (Laburthe, M.,Trends Endocrinol Metab. 1(3):168-74 (1990), mediates intestinalsecretion (Cox, H. M., et al., Br J Pharmacol 101(2):247-52 (1990);Playford, R. J., et al., Lancet 335(8705):1555-7 (1990)), stimulate netabsorption (MacFayden, R. J., et al., Neuropeptides 7(3):219-27 (1986)),and two major in vivo variants (PYY and PYY₃₋₃₆) have been identified(e.g., Eberlein, G. A., et al., Peptides 10 (4), 797-803 (1989)). Thesequence of PYY, as well as analogs and derivatives thereof, includingPYY₃₋₃₆, are known in the art (e.g., U.S. Pat. Nos. 5,574,010 and5,552,520). For ease of reference herein, the family of PYYpolypeptides, PYY derivatives, variants and analogues are referred tocollectively as PYY. Examples of PYY particle formulations are given inExamples 3 and 4B.

Oxyntomodulin is a naturally occurring 37 amino acid peptide hormonefound in the colon that has been found to suppress appetite andfacilitate weight loss (Wynne K, et al., Int J Obes (Lond)30(12):1729-36 (2006)). The sequence of oxyntomodulin, as well asanalogs and derivatives thereof, are known in the art (e.g., U.S. PatentPublication Nos. 2005-0070469 and 2006-0094652). For ease of referenceherein, the family of oxyntomodulin polypeptides, oxyntomodulinderivatives, variants and analogues are referred to collectively asoxyntomodulin. Examples of oxyntomodulin particle formulations are givenin Examples 2 and 4A.

GIP is an insulinotropic peptide hormone (Efendic, S., et al., HormMetab Res. 36:742-6 (2004)) and is secreted by the mucosa of theduodenum and jejunum in response to absorbed fat and carbohydrate thatstimulate the pancreas to secrete insulin. GIP circulates as abiologically active 42-amino acid peptide. GIP is also known asglucose-dependent insulinotropic protein. GIP is a 42-amino acidgastrointestinal regulatory peptide that stimulates insulin secretionfrom pancreatic beta cells in the presence of glucose (Tseng, C., etal., PNAS 90:1992-1996 (1993)). The sequence of GIP, as well as analogsand derivatives thereof, are known in the art (e.g., Meier J. J.,Diabetes Metab Res Rev. 21(2):91-117 (2005); Efendic S., Horm Metab Res.36(11-12):742-6 (2004)). For ease of reference herein, the family of GIPpolypeptides, GIP derivatives, variants and analogues are referred tocollectively as GIP.

Amylin, as well as analogs and derivatives thereof, are known in the art(e.g., U.S. Pat. Nos. 5,686,411, 5,814,600, 5,998,367, 6,114,304,6,410,511, 6,608,029, and 6,610,824). For ease of reference herein, thefamily of amylin polypeptides, amylin derivatives, variants andanalogues are referred to collectively as amylin.

The cDNA sequence encoding the human leptin protein hormone is known(e.g., Masuzaki, H., et al. (Diabetes 44: 855-858, 1995)). Leptin, aswell as analogs and derivatives thereof, are known in the art (e.g.,U.S. Pat. Nos. 5,521,283, 5,525,705, 5,532,336, 5,552,522, 5,552,523,5,552,524, 5,554,727, 5,559,208, 5,563,243, 5,563,244, 5,563,245,5,567,678, 5,567,803, 5,569,743, 5,569,744, 5,574,133, 5,580,954,5,594,101, 5,594,104, 5,605,886, 5,691,309, and 5,719,266; P.C.T.International Patent Publication Nos. WO96/22308, WO96/31526,WO96/34885, 97/46585, WO97/16550, and WO 97/20933; European PatentPublication No. EP 0 741 187). For ease of reference herein, the familyof leptin polypeptides, leptin derivatives, variants and analogues arereferred to collectively as leptin.

The beneficial agents can also be in various forms including, but notlimited to, the following: uncharged molecules; components of molecularcomplexes; and pharmacologically acceptable salts such as hydrochloride,hydrobromide, sulfate, laurates, palmatates, phosphate, nitrate, borate,acetate, maleate, tartrate, oleates, or salicylates. For acidic drugs,salts of metals, amines or organic cations, for example, quaternaryammonium, can be employed. Furthermore, simple derivatives of the drugsuch as esters, ethers, amides and the like that have solubilitycharacteristics suitable for the purpose of the invention can also beused herein. Drug or other formulation within the osmotic deliverydevice beneficial agent chamber can have various art known forms such assolution, dispersion, paste, cream, particle, granule, tablet,emulsions, suspensions, powders and the like. In addition to the one ormore beneficial agents, the beneficial agent formulation may optionallyinclude pharmaceutically acceptable carriers and/or additionalingredients such as antioxidants, stabilizing agents, buffers, andpermeation enhancers.

The above agents are useful for the treatment of a variety of conditionsincluding but not limited to hemophilia and other blood disorders,growth disorders, diabetes, leukemia and lymphoma, hepatitis, renalfailure, bacterial infection, viral infection (e.g., infection by HIV,HCV, etc.), hereditary diseases such as cerbrosidase deficiency andadenosine deaminase deficiency, hypertension, septic shock, autoimmunediseases (e.g., Graves disease, systemic lupus erythematosus andrheumatoid arthritis), shock and wasting disorders, cystic fibrosis,lactose intolerance, Crohn's disease, inflammatory bowel disease,Alzheimer's disease, metabolic disorders (such as obesity), and cancers.

The amount of beneficial agent employed in the delivery device of theinvention is that amount necessary to deliver a therapeuticallyeffective amount of the agent to achieve the desired therapeutic result.In practice, this will vary depending upon such variables, for example,as the particular agent, the site of delivery, the severity of thecondition, and the desired therapeutic effect. Beneficial agents andtheir dosage unit amounts are known to the prior art in Goodman &Gilman's The Pharmacological Basis of Therapeutics, 11th Ed., (2005),McGraw Hill; Remington's Pharmaceutical Sciences, 18th Ed., (1995), MackPublishing Co.; and Martin's Physical Pharmacy and PharmaceuticalSciences, 1.00 edition (2005), Lippincott Williams & Wilkins. Typically,for an osmotic delivery device, the volume of a beneficial agent chambercomprising the beneficial agent formulation (e.g., chamber 108, FIG. 1)is between about 50 μl to about 1000 μl, more preferably between about100 μl and about 500 μl, more preferably between about 150 μl and about200 μl.

The vehicle for the beneficial agents typically comprises a non-aqueous,single-phase vehicle including one or more polymer and one or moresolvent. The vehicle preferably exhibits viscous fluid characteristics.A polypeptide component may, for example, be in a particle formulationthat is uniformly dispersed in the vehicle. Typically, the particleformulation includes a stabilizing component comprising one of morestabilizer component selected from the group consisting ofcarbohydrates, antioxidants, amino acids, buffers, and inorganiccompounds.

2.2.2 Particle Formulations

For some beneficial agents, in particular polypeptides, particleformulations are used in the practice of the present invention. Particleformulations are preferably chemically and physically stable for atleast about one month, more preferably at least about three months, morepreferably at least about six months, and even more preferably at leastabout 12 months, at delivery temperature. The delivery temperature istypically normal human body temperature, for example, about 37° C., orslightly higher, for example, about 40° C. Further, particleformulations of the present invention are preferably chemically andphysically stable for at least about three months, more preferably atleast about six months, even more preferably at least about 12 months,at storage temperature. Examples of storage temperatures includerefrigeration temperature, for example, about 5° C., or roomtemperature, for example, about 25° C.

A particle formulation may be considered chemically stable if less thanabout 25%, preferably less than about 20%, more preferably less thanabout 15%, more preferably less than about 10%, and more preferably lessthan about 5% breakdown products of the peptide particles are formedafter about three months, preferably after about six months, preferablyafter about 12 months at delivery temperature and after about sixmonths, after about 12 months, and preferably after about 24 months atstorage temperature.

A particle formulation may be considered physically stable if less thanabout 10%, preferably less than about 5%, more preferably less thanabout 3%, more preferably less than 1% aggregates of the peptideparticles are formed after about three months, preferably after aboutsix months, at delivery temperature and about six months, preferablyabout 12 months, at storage temperature. Another criterion fordemonstrating that a particle formulation is considered physicallystable is that the solid state of the particle can remain essentiallythe same or substantially similar (for example, the particle does notdemonstrate a phase transition from amorphous to crystal or aninter-exchange between polymorphous states) for a selected period oftime (e.g., after about three months, preferably after about six months,preferably after about 12 months at delivery temperature and after aboutsix months, preferably after about 12 months, and more preferably afterabout 24 months at storage temperature).

To preserve protein stability generally a protein solution is kept in afrozen condition and lyophilized or spray dried to a solid state. Tg(glass transition temperature) may be one factor to consider inachieving stable compositions of protein. While not intending to bebound by any particular theory, the theory of formation of a high Tgamorphous solid to stabilize peptides, polypeptides, or proteins hasbeen utilized in pharmaceutical industry. Generally, if an amorphoussolid has a higher Tg, such as 100° C., protein products will not havemobility when stored at room temp or even at 40° C. because the storagetemperature is below the Tg. Calculations using molecular informationhave shown that if a glass transition temperature is above a storagetemperature of 50° C. that there is zero mobility for molecules. Nomobility of molecules correlates with no instability issues. Tg is alsodependent on the moisture level in the product formulation. Generally,the more moisture, the lower the Tg of the composition.

Accordingly, in some aspects of the present invention, excipients withhigher Tg may be included in the protein formulation to improvestability, for example, sucrose (Tg=75° C.) and trehalose (Tg=110° C.).Preferably, particle formulations are formable into particles usingprocesses such as spray drying, lyophilization, desiccation,freeze-drying, milling, granulation, ultrasonic drop creation,crystallization, precipitation, or other techniques available in the artfor forming particles from a mixture of components. The particles arepreferably substantially uniform in shape and size.

A typical spray dry process may include, for example, loading a spraysolution containing a peptide, for example, omega interferon, andstabilizing excipients into a sample chamber. The sample chamber istypically maintained at a desired temperature, for example,refrigeration to room temperature. Refrigeration generally promotesstability of the protein. A feed pump sprays the spray solution into anozzle atomizer. At the same time, atomized gas (typically, air,nitrogen, or inert gas) is directed at the outlet of the nozzle atomizerto form a mist of droplets from the spray solution. The mist of dropletsis immediately brought into contact with a drying gas in a dryingchamber. The drying gas removes solvent from the droplets and carriesthe particles into a collection chamber. In spray drying, factors thatcan affect yield include, but are not limited to, localized charges onparticles (which may promote adhesion of the particles to the spraydryer) and aerodynamics of the particles (which may make it difficult tocollect the particles). In general, yield of the spray dry processdepends in part on the particle formulation.

The particles are sized such that they can be delivered via an osmoticdelivery system of the present invention. Uniform shape and size of theparticles typically help to provide a consistent and uniform rate ofrelease from such a delivery system; however, a particle preparationhaving a non-normal particle size distribution profile may also be used.For example, in the osmotic delivery devices described herein, the sizeof the particles is less than about 30%, preferably is less than about20%, preferably is less than about than 10%, and more preferably lessthan about 5% of the diameter of the delivery (or exit) orifice.

In a preferred embodiment, when the particles are suspended in a vehiclethey do not settle in less than about three months at deliverytemperature. Generally speaking, smaller particles tend to have a lowersettling rate in viscous vehicles than larger particles. Accordingly,micron- to nano-sized particles are typically desirable. In anembodiment of the particle formulation for use with an osmotic deliverysystem, wherein the delivery orifice diameter of the implant is in arange of, for example, about 0.1 to about 0.5 mm, particle sizes may bepreferably less than about 50 microns, more preferably less than about10 microns, more preferably in a range from about 3 to about 7 microns.In one embodiment, the orifice is about 0.25 mm (about 250 μm) and theparticle size is approximately 3-5 μm.

In some aspects of the present invention, a particle formulationcomprises one or more polypeptide, one or more stabilizers, andoptionally a buffer. The stabilizers may be, for example, carbohydrate,antioxidant, amino acid, buffer, or inorganic compound. In a preferredembodiment, the carbohydrate is a disaccharide (e.g., sucrose), theantioxidant is an amino acid (e.g., methionine), and the buffer is anorganic buffer (e.g., citrate). The amounts of stabilizers and buffer inthe particle formulation can be determined experimentally based on theactivities of the stabilizers and buffers and the desiredcharacteristics of the formulation. Typically, the amount ofcarbohydrate in the formulation is determined by aggregation concerns.In general, the carbohydrate level is not be too high so as to avoidpromoting crystal growth in the presence of water due to excesscarbohydrate unbound to the peptide. Typically, the amount ofantioxidant in the formulation is determined by oxidation concerns,while the amount of amino acid in the formulation is determined byoxidation concerns and/or formability of particles during spray drying.Typically, the amount of buffer in the formulation is determined bypre-processing concerns, stability concerns, and formability ofparticles during spray drying. Buffer may be required to stabilize thepeptide during processing, e.g., solution preparation and spray drying,when all excipients are solubilized.

Examples of carbohydrates that may be included in the particleformulation include, but are not limited to, monosaccharides (e.g.,fructose, maltose, galactose, glucose, D-mannose, and sorbose),disaccharides (e.g., lactose, sucrose, trehalose, and cellobiose),polysaccharides (e.g., raffinose, melezitose, maltodextrins, dextrans,and starches), and alditols (acyclic polyols; e.g., mannitol, xylitol,maltitol, lactitol, xylitol sorbitol, pyranosyl sorbitol, andmyoinsitol). Preferred carbohydrates include non-reducing sugars such assucrose, trehalose, and raffinose.

Examples of antioxidants that may be included in the particleformulation include, but are not limited to, methionine, ascorbic acid,sodium thiosulfate, catalase, platinum, ethylenediaminetetraacetic acid(EDTA), citric acid, cysteins, thioglycerol, thioglycolic acid,thiosorbitol, butylated hydroxanisol, butylated hydroxyltoluene, andpropyl gallate.

Examples of amino acids that may be included in the particle formulationinclude, but are not limited to, arginine, methionine, glycine,histidine, alanine, L-leucine, glutamic acid, iso-leucine, L-threonine,2-phenylamine, valine, norvaline, praline, phenylalanine, tryptophan,serine, asparagines, cysteine, tyrosine, lysine, and norleucine.Preferred amino acids include those that readily oxidize, e.g.,cysteine, methionine, and tryptophan.

Examples of buffers that may be included in the particle formulationinclude, but are not limited to, citrate, histidine, succinate,phosphate, maleate, tris, acetate, carbohydrate, and gly-gly. Preferredbuffers include citrate, histidine, succinate, and tris.

Examples of inorganic compounds that may be included in the particleformulation include, but are not limited to, NaCl, NaSCN, Na₂SO₄,NaHCO₃, KCl, KH₂PO₄, CaCl₂, and MgCl₂.

In addition, the particle formulation may include other excipients suchas surfactants, bulking agents, and salts. Examples of surfactantsinclude, but are not limited to, Polysorbate 20, Polysorbate 80,PLURONIC™ (BASF Corporation, Mount Olive, N.J.) F68, and sodium docecylsulfate (SDS). Examples of bulking agents include, but are not limitedto, mannitol and glycine. Examples of salts include, but are not limitedto, sodium chloride, calcium chloride, and magnesium chloride.

2.2.3 Vehicle Formulations

In one aspect of the present invention, a vehicle (e.g., a suspensionvehicle) provides a stable environment in which a beneficial agent(e.g., a small molecule and/or polypeptide particles) is dispersed. Thevehicle typically comprises one or more polymer and one or more solventthat together form a solution of sufficient viscosity to uniformlysuspend the beneficial agent(s). The piston assemblies of the presentinvention, as described herein above, are substantially impermeable toand substantially resistant to leaching when exposed to the vehicle,particularly to the organic solvent of the vehicle.

The viscosity of the vehicle is typically sufficient to prevent thebeneficial agent from settling during storage and use in a method ofdelivery, for example, in the osmotic delivery devices. The vehicle isbiodegradable in that the vehicle disintegrates or breaks down over aperiod of time in response to a biological environment. Thedisintegration of the vehicle may occur by one or more physical orchemical degradative processes such as by enzymatic action, oxidation,reduction, hydrolysis (e.g., proteolysis), displacement (e.g., ionexchange), or dissolution by solubilization, emulsion or micelleformation. After the vehicle disintegrates, components of the vehicleare absorbed or otherwise dissipated by the body and surrounding tissueof the subject.

The solvent in which the polymer is dissolved may affect characteristicsof the beneficial agent formulation such as the behavior of thebeneficial agent formulation during storage. A solvent may be selectedin combination with a polymer so that the resulting vehicle exhibitsphase separation upon contact with the aqueous environment. Optionally,the solvent may be selected in combination with the polymer so that theresulting vehicle exhibits phase separation upon contact with theaqueous environment having less than approximately about 10% water.

In some embodiments, the solvent may be an acceptable solvent that isnot miscible with water. The solvent may also be selected so that thepolymer is soluble in the solvent at high concentrations such as at apolymer concentration of greater than about 30%. However, typically thepeptide is substantially insoluble in the solvent. Examples of solventsuseful in the practice of the present invention include, but are notlimited to, lauryl alcohol, benzyl benzoate, benzyl alcohol, lauryllactate, decanol (also called decyl alcohol), ethyl hexyl lactate, andlong chain (C₈ to C₂₄) aliphatic alcohols, esters, carboxylic acidesters, fatty acid esters, or mixtures thereof. The solvent used in thevehicle may be “dry,” in that it has a low moisture content. Preferredsolvents for use in formulation of the vehicle include lauryl lactate,lauryl alcohol, and benzyl benzoate.

Additional solvents that may be useful in the practice of the presentinvention include, but are not limited to, the following: vegetable oils(sesame oil, cottonseed oil, soybean oil); triglycerides; glycerin;glycerol; polyethylene glycol (e.g., PEG400); glycofurol;N-methylpyrrolidone; polysorbates (e.g., polysorbate 20 and polysorbate80); alpha-tocopherol (e.g., Vitamin E); dimethyl sulfoxide; sucroseacetate isobutyrate (SAIB); or silicon medical fluid.

Examples of polymers for formulation of the vehicles of the presentinvention include, but are not limited to, a polyester (e.g., polylacticacid or polylacticpolyglycolic acid), a polymer comprising pyrrolidone(e.g., polyvinylpyrrolidone (PVP) having a molecular weight ranging fromapproximately 2,000 to approximately 1,000,000), ester or ether of anunsaturated alcohol (e.g., vinyl acetate),polyoxyethylenepolyoxypropylene block copolymer, or mixtures thereof. Inone embodiment, the polymer is PVP having a molecular weight of 2,000 to1,000,000. The polymer used in the vehicle may include one or moredifferent polymers or may include different grades of a single polymer.The polymer used in the vehicle may also be dry or have a low moisturecontent.

Generally speaking, a vehicle according to the present invention mayvary in composition based on the desired performance characteristics. Inone embodiment, the vehicle may comprise about 25 wt % to about 80 wt %polymer and about 75 wt % to about 20 wt % solvent, more preferably 40wt % to about 75 wt % polymer and about 60 wt % to about 25 wt %solvent. Preferred embodiments of a vehicle include vehicles formed ofpolymer and solvent combined at the following ratios: about 75 wt %polymer and about 25 wt % solvent; about 60 wt % polymer and about 40 wt% solvent; about 55 wt % polymer and about 45 wt % solvent; about 50 wt% polymer and about 50 wt % solvent; about 45 wt % polymer and about 55wt % solvent; about 40 wt % polymer and about 60 wt % solvent; and about25 wt % polymer and about 75 wt % solvent. In a preferred embodiment thesolvent is benzyl benzoate and the polymer is PVP.

The vehicle may exhibit Newtonian behavior. The vehicle is typicallyformulated to provide a viscosity that maintains a uniform dispersion ofthe beneficial agent(s) for a predetermined period of time in abeneficial agent formulation. This helps facilitate making a beneficialagent formulation tailored to provide controlled delivery of the peptideat a desired rate. The viscosity of the vehicle may vary depending onthe desired application, the size and type of the particle formulation,and the loading of the particle formulation in the vehicle. Theviscosity of the vehicle may be varied by altering the type or relativeamount of the solvent or polymer used.

The vehicle may have a viscosity ranging from about 100 poise to about1,000,000 poise, preferably from about 1,000 poise to about 100,000poise. The viscosity may be measured at 37° C., at a shear rate of10.sup.−4/sec, using a parallel plate rheometer. In one embodiment, theviscosity of the vehicle ranges from approximately 5,000 poise toapproximately 50,000 poise. In one embodiment, the vehicle has aviscosity of about 16,700 poise at 33° C. In preferred embodiments, theviscosity range is between about 12,000 to about 18,000 poise at 33° C.

The vehicle may exhibit phase separation when contacted with the aqueousenvironment. However, typically the vehicle exhibits substantially nophase separation as a function of temperature. For example, at atemperature ranging from approximately 0° C. to approximately 70° C. andupon temperature cycling, such as cycling from 4° C. to 37° C. to 4° C.,the vehicle typically exhibits no phase separation. In some embodimentsof the invention, the vehicle exhibits phase separation when contactedwith the aqueous environment having less than approximately 10% water.

The vehicle may be, for example, prepared by combining the polymer andthe solvent under dry conditions such as in a dry box. The polymer andsolvent may be combined at an elevated temperature, for example, fromapproximately 40° C. to approximately 70° C., and allowed to liquefy andform the single phase. The ingredients may be blended under vacuum toremove air bubbles produced from the dry ingredients. The ingredientsmay be combined using a conventional mixer such as a dual helix blade orsimilar mixer, for example, set at a speed of approximately 40 rpm.However, higher speeds may also be used to mix the ingredients. Once aliquid solution of the ingredients is achieved, the vehicle may becooled to room temperature. Differential scanning calorimetry (DSC) maybe used to verify that the vehicle is a single phase. Further, thecomponents of the vehicle (e.g., the solvent and/or the polymer) may betreated to substantially reduce or substantially remove peroxides (e.g.,by treatment with methionine; e.g., U.S. Patent Application PublicationNo. 2007-0027105).

The beneficial agent(s) (e.g., a small molecule and/or particleformulation) is added to the vehicle to form a beneficial agentformulation. The beneficial agent formulation may be prepared bydispersing the beneficial agent(s) in the vehicle. The vehicle may beheated and the beneficial agent(s) added to the vehicle under dryconditions. The ingredients may be mixed under vacuum at an elevatedtemperature such as from about 40° C. to about 70° C. The ingredientsmay be mixed at a sufficient speed such as from about 40 rpm to about120 rpm, and for a sufficient amount of time, for example, about 15minutes, to achieve a uniform dispersion of the beneficial agent(s) inthe vehicle. The mixer may be a dual helix blade or other suitablemixer. The resulting mixture may be removed from the mixer, sealed in adry container to prevent water from contaminating the beneficial agentformulation, and allowed to cool to room temperature before further use,for example, loading into an osmotic delivery system.

The beneficial agent formulation typically has an overall moisturecontent of less than about 10 wt %, preferably less than about 5 wt %,and more preferably less than about 4 wt %.

In summary, the components of the vehicle provide biocompatibility withthe subject in whom use is intended. Components of the vehicle offersuitable chemico-physical properties to form stable formulations ofbeneficial agents. These properties include, but are not limited to, thefollowing: viscosity of the vehicle (which may include the viscosity ofthe vehicle plus beneficial agent); purity of the vehicle; residualmoisture of the vehicle; density of the vehicle; compatibility with thebeneficial agent(s); compatibility with implantable devices; molecularweight of the polymer; stability of the vehicle; and hydrophobicity andhydrophilicity of the vehicle. These properties can be manipulated andcontrolled, for example, by variation of the vehicle composition andmanipulation of the ratio of components used in the vehicle.

All components included in the particle formulation are typicallyacceptable for pharmaceutical use in subjects, particularly humans.

Some additional examples of suitable solvents, polymers, beneficialagents, and particle formulations have been described (e.g., U.S. Pat.Nos. 5,972,370, 5,932,547, 6,730,328, 7,258,869; and U.S. PatentApplication Publication Nos. 2004-0224903, 2005-0008661, 2005-0112188,2006-0193918, 2006-0216242, 2006-0263433, 2006-0251618).

2.2.4 Combined Formulations

In some embodiments of the present invention, a single beneficial agentin a solution or formulation is used to fill a beneficial agent chamberof an osmotic delivery device, for example, two or more osmotic deliverydevices, wherein each delivery device has a single beneficial agentchamber, can be used to delivery a single beneficial agent from eachosmotic delivery device in order to achieve delivery of two or morebeneficial agents. In this case, each osmotic delivery device delivers asolution or suspension formulation comprising a different beneficialagent. In other embodiments of the present invention, a single osmoticdelivery device may be employed wherein each device has two or morebeneficial agent reservoirs. In this case, a single beneficial agent canbe delivered from one beneficial agent chamber, a different beneficialagent from beneficial agent chamber, and so on.

In another aspect the present invention relates to formulations ofbeneficial agents wherein two or more beneficial agents are provided incombination in a single solution or suspension formulation (i.e., acombined beneficial agent suspension formulation). The present inventionrelates to methods of making these formulations, the formulationsthemselves, and use of the formulations in osmotic delivery devices, forexample, as described herein. This aspect of the invention provides fourbasic formulation modifications the description of which follow hereinbelow.

First, two or more beneficial agents may be dissolved directly in thevehicle. Typically, small molecule beneficial agents are most suited tothis method of preparing a solution formulation. Small polypeptides arealso often suited to this method. An example of such a formulation isproviding a dimethylsulfoxide (DMSO)-based vehicle in which a smallpolypeptide, such as leuprolide acetate, is dissolved along with asecond small polypeptide, such as goserelin acetate, wherein both of thesmall polypeptides are soluble in the vehicle.

Second, one or more beneficial agent may be dissolved in a vehicle andone or more beneficial agent formulated into particles may be suspendedin a vehicle. Typically, small molecules and small polypeptides are mostsuited to be dissolved in the suspension vehicle. Components of suitableparticle formulations for a beneficial agent, which are not able to bedissolved in the vehicle, can be selected as described herein above. Abeneficial agent may not, for example, be stable in a solutionformulation and therefore may need to be stabilized in a particle formfor suspension. In one embodiment, a first beneficial agent can bedissolved in the vehicle thus allowing maximum loading of particles thatcontain a second beneficial agent. By dissolving the first beneficialagent in the vehicle the loading potential of the particle containingthe second beneficial agent is typically not diminished. Thiscombination maximizes the amount of the two beneficial agents that canbe delivered from an osmotic delivery device with, for example, onebeneficial agent reservoir. If the dissolved beneficial agent affectsthe viscosity of the suspension vehicle, the components of thesuspension vehicle can be altered to accommodate the change inviscosity, for example, by increasing or decreasing the amount of apolymer in the vehicle that is used to increase viscosity of thevehicle. An example of such a formulation would be dissolving a smallmolecule antiviral drug such as Telaprevir (VX-950; VertexPharmaceuticals, Inc., Cambridge, Mass.) in the non-aqueous organicsolvent-based vehicle, such as lauryl alcohol and povidone, anddispersing particles comprising an interferon, such as an alphainterferon or omega interferon, in the vehicle.

Third, two or more beneficial agents can be combined in one particleformulation. In situations where the beneficial agents (i) can bestabilized in a particle formulation having the same components, and(ii) do not adversely affect each other's stability, then the beneficialagents can be combined in a single particle that can be suspended in avehicle. For example, this method is suited to the formation of twopolypeptides into a single particle formulation, such as, twointerferons. Another example is the formulation of two polypeptides intoa single particle wherein each of the polypeptides provides atherapeutic benefit for different aspect of a single disease orcondition, for example, (i) exendin-4 and oxyntomodulin (Example 4A) orexendin-4 and PYY (Example 4B) for the treatment of diabetes or tofacilitate or promote weight loss, or (ii) leptin and amylin tofacilitate or promote weight loss, for example, in obese or overweightsubjects. Another example is the formulation of two or more polypeptidesinto a single particle wherein each of the polypeptides provides atherapeutic benefit for different aspect of a single disease orcondition, for example, (i) exendin-4, oxyntomodulin, and PYY for thetreatment of diabetes or to facilitate or promote weight loss, (ii)leptin and amylin and PYY to facilitate or promote weight loss, forexample, in obese or overweight subjects.

Fourth, two or more beneficial agents can be formulated individuallyinto different particle formulations. The components of the particleformulations, other than the beneficial agent, may be the same ordifferent. The different particle formulation can then be suspended inthe same suspension vehicle, thus providing a single suspensionformulation comprising two different particle formulations, wherein eachparticle formulation has different beneficial agents. For example, thismethod is suited to the formation of two polypeptides each in adifferent particle formulation, such as, exendin-4 in one particleformulation, and oxyntomodulin or PYY in a second particle formulation,wherein the two particle formulations are combined in a singlesuspension formulation and administered to facilitate or promote weightloss, for example, in obese or overweight subjects. As another example,this method is suited to the formation of two polypeptides each in adifferent particle formulation, such as, leptin in one particleformulation, and amylin in a second particle formulation, wherein thetwo particle formulations are combined in a single suspensionformulation and administered to facilitate or promote weight loss. Oneadvantage of preparing particle formulations comprising singlebeneficial agents is that the relative proportions of the differentparticle formulations can be varied to maximize therapeutic effect ofthe different beneficial agents. For example, the amount of a particleformulation with a first beneficial agent may be greater than, equal to,or less than the amount of the particle formulation with a secondbeneficial agent in a suspension formulation comprising both of theparticle formulations. An example is the formulation of two or morepolypeptides into two or more particles wherein each of the polypeptidesprovides a therapeutic benefit for different aspect of a single diseaseor condition, for example, (i) exendin-4 in a first particle formulationand oxyntomodulin or PYY in a second particle formulation, the particleformulations combined in a single suspension vehicle for the treatmentof diabetes or to facilitate or promote weight loss, (ii) exendin-4 in afirst particle formulation, oxyntomodulin in the first particleformulation, and PYY in a second particle formulation, the particleformulations combined in a single suspension vehicle administered tofacilitate or promote weight loss, for example, in obese or overweightsubjects, (iii) leptin in a first particle formulation and amylin in asecond particle formulation, the particle formulations combined in asingle suspension vehicle administered to facilitate or promote weightloss, or (iv) leptin in a first particle formulation, amylin in thefirst particle formulation, and PYY in a second particle formulation,the particle formulations combined in a single suspension vehicleadministered to facilitate or promote weight loss.

These four modifications can also be combined, for example, one or morebeneficial agent may be soluble in the vehicle and this may be combinedwith a particle formulation suspended in the vehicle, wherein theparticle formulation comprises two or more beneficial agents. Inaddition to the examples given above, some further examples ofcombinations that may be employed in one or more of the above-describedcombined formulations include, but are not limited to, the following:(i) combining a Her-2 blocker (e.g. lapatinib, which is a smallmolecule) and a platelet-derived growth factor blocker (e.g., imatinib)together in a formulation to treat her-2 sensitive tumors; (ii)combining a small antibody fragment directed against vascularendothelial growth factor with an antibody fragment directed Her-2 totreat her-2 sensitive tumors; and (iii) combining ribavirin with aninterferon (e.g., omega interferon) for the treatment of viral disease(e.g., hepatitis C virus infection).

Suitable components for vehicles (e.g., solvents and polymers),beneficial agents, and components for particle formulations (e.g.,carbohydrate, antioxidants, amino acids, and buffers) have beendescribed herein above.

The present invention also includes methods of manufacturing theformulations of the present invention, including the particleformulations, vehicles, and beneficial agent formulations (including,but not limited to suspension formulations) described herein above.

2.3 Examples of Administration of Multiple Beneficial Agents forTreating Diseases or Conditions

As discussed herein above, the administration of multiple beneficialagents can be accomplished by several approaches including, for example,(i) delivery of combined formulations of the beneficial agents from anosmotic delivery device with a single beneficial agent chamber, (ii)delivery of individual formulations of each beneficial agent fromindividual osmotic delivery devices each having a single beneficialagent chamber, (iii) delivery of individual formulations of eachbeneficial agent from an osmotic delivery device having a beneficialagent chamber for each beneficial agent formulation, or (iv) delivery ofcombined formulations of beneficial agents from an osmotic deliverydevice having a beneficial agent chamber for each combined beneficialagent formulation.

Typically, an osmotic delivery device is implanted within the subject,for example, subcutaneously. The device(s) can be insertedsubcutaneously into either or both arms (e.g., in the inside, outside,or back of the upper arm) or the abdomen. Preferred locations in theabdomen are under the abdominal skin in the area extending below theribs and above the belt line. To provide a number of locations forinsertion of one or more osmotic delivery device within the abdomen, theabdominal wall can be divided into 4 quadrants as follows: the upperright quadrant extending 5-8 centimeters below the right ribs and about5-8 centimeters to the right of the midline, the lower right quadrantextending 5-8 centimeters above the belt line and 5-8 centimeters to theright of the midline, the upper left quadrant extending 5-8 centimetersbelow the left ribs and about 5-8 centimeters to the left of themidline, and the lower left quadrant extending 5-8 centimeters above thebelt line and 5-8 centimeters to the left of the midline. This providesmultiple available locations for implantation of one or more devices onone or more occasions.

Following here are several examples of how the osmotic delivery devicesand formulations of the present invention may be combined to treat aselected disease or condition.

In one embodiment, the formulations and osmotic delivery devices of thepresent invention can be administered to facilitate or promote weightloss, for example, in obese or overweight subjects. The presentinvention provides methods of treating or preventing disorders orconditions associated with an undesirable level of a satiety factor byadministering to a subject in need thereof an effective amount of anagonist or antagonist of a satiety factor. Exemplary disorders orconditions associated with an undesirable level of a satiety factorinclude overweight, obesity, metabolic disorders, hypertension, lipidrelated disorders, anorexia and type II diabetes.

Administration of amylin appears to restore leptin responsivity inobesity (e.g., J. Roth, et al., 66th Annual Scientific Sessions of theAmerican Diabetes Association (ADA), Washington, D.C., abstract number52-LB). Accordingly, co-administration of leptin with amylin may providea useful treatment of obesity by, for example, reduction of body weightand/or body fat in treated subjects, as well facilitating or promotingweight loss, for example, in overweight subjects.

The formulations and osmotic delivery devices of the present inventionmay be employed to treat Type II diabetes and/or facilitate or promoteweight loss, for example, in obese or overweight subjects, in a numberof ways. A few examples, in view of the teachings presented herein, areas follows. First, a particle formulation comprising amylin (e.g.,pramlintide acetate) is prepared and a particle formulation comprisingleptin is prepared. Each particle formulation may, for example,comprise, a carbohydrate (e.g., sucrose), an antioxidant (e.g.,methionine), and a buffer (e.g., citrate) in addition to the beneficialagent. Each particle formulation is suspended in a vehicle (for example,comprising benzyl benzoate and polyvinylpyrrolidone). Each of thesuspensions is loaded into an osmotic delivery device (e.g., as shown inFIG. 1), wherein the osmotic delivery device has a single beneficialagent chamber. Thus two osmotic delivery devices are provided, oneloaded with a suspension formulation comprising amylin and one loadedwith a suspension formulation comprising leptin. The two osmoticdelivery devices are then implanted in a subject to facilitate orpromote weight loss, for example, in an obese or overweight subject inneed of treatment.

Second, an exendin-4 particle formulation (Example 1) and anoxyntomodulin particle formulation (Example 2) are each dispersed in avehicle to provide a suspension formulation (Example 7A). The suspensionformulation is then loaded into the beneficial agent chamber of anosmotic delivery device, for example, the device illustrated in FIG. 1,chamber 16.

Third, an exendin-4 particle formulation (Example 1) and PYY particleformulation (Example 3) are each dispersed throughout a vehicle toprovide a suspension formulation (Example 7B). The suspensionformulation is then loaded into the beneficial agent chamber of anosmotic delivery device, for example, the device illustrated in FIG. 1,chamber 16.

In an alternate embodiment, a particle formulation comprising two ormore beneficial agents is prepared. In one example, two beneficialagents are amylin and leptin. The particle formulation may, for example,comprise, a carbohydrate (e.g., sucrose), an antioxidant (e.g.,methionine), and a buffer (e.g., citrate) in addition to the beneficialagents. The particle formulation is suspended in a vehicle (for example,comprising benzyl benzoate and polyvinylpyrrolidone). The suspensions isloaded into an osmotic delivery device (e.g., as shown in FIG. 1),wherein the osmotic delivery device has a single beneficial agentchamber. Thus a single osmotic delivery device is provided loaded with asuspension formulation comprising amylin and leptin. The osmoticdelivery device is then implanted in a subject.

As a second example, a single particle formulation comprising bothexendin and oxyntomodulin (Example 4A) is dispersed throughout a vehicleto provide a suspension formulation (Example 7C). The suspensionformulation is then loaded into the beneficial agent chamber of anosmotic delivery device, for example, the device illustrated in FIG. 1,chamber 16.

As a third example, a single particle formulation comprising exendin-4and PYY (Example 4B) is dispersed throughout a vehicle to provide asuspension formulation (Example 7D). The suspension formulation is thenloaded into the beneficial agent chamber of an osmotic delivery device,for example, the device illustrated in FIG. 1, chamber 16.

In another embodiment, each of the suspension formulations justdescribed are loaded into one osmotic delivery device having multiple,for example, two beneficial agent chambers wherein one suspensionformulation is loaded into one beneficial agent chamber. As a firstexample, a single osmotic delivery device is provided wherein onebeneficial agent chamber is loaded with a suspension formulationcomprising amylin and the other beneficial agent chamber is loaded witha suspension formulation comprising leptin.

As a second example, an exendin-4 particle formulation (Example 1) isdispersed throughout a vehicle to provide a suspension formulation. Thesuspension formulation is then loaded into a first beneficial agentchamber of an osmotic delivery device, for example, as described in FIG.3, chamber 330 (Example 8A). An oxyntomodulin particle formulation(Example 2) is dispersed throughout the vehicle to provide a suspensionformulation. The suspension formulation is then loaded into a secondbeneficial agent chamber of an osmotic delivery device, for example, asdescribed in FIG. 3, chamber 340 (Example 8A). A PYY particleformulation (Example 3) is dispersed throughout a vehicle to provide asuspension formulation. The suspension formulation is then loaded into athird beneficial agent chamber of an osmotic delivery device, forexample, as described in FIG. 3, chamber 350 (Example 8A).

As a third example, an alpha interferon particle formulation (Example 5)is dispersed throughout a vehicle to provide a suspension formulation.The suspension formulation is then loaded into a first beneficial agentchamber of an osmotic delivery device, for example, as described in FIG.4, chamber 450 (Example 8B). An Amphotericin B solution formulation(Example 6A) is then loaded into a second beneficial agent chamber of anosmotic delivery device, for example, as described in FIG. 4, chamber460 (Example 8B).

As a fourth example, an alpha interferon particle formulation (Example5) is dispersed throughout a vehicle to provide a suspensionformulation. The suspension formulation is then loaded into a firstbeneficial agent chamber of an osmotic delivery device, for example, asdescribed in FIG. 4, chamber 450 (Example 8C). An Amphotericin Bformulation (Example 6B) is then loaded into a second beneficial agentchamber of an osmotic delivery device, for example, as described in FIG.4, chamber 460 (Example 8C).

Numerous examples of osmotic delivery devices having two beneficialagent chambers are provided herein (e.g., FIG. 4A, FIG. 5A, FIG. 6, andFIG. 7A). The single osmotic delivery device is then implanted in asubject to achieve treatment of a disease or condition.

Many disease or conditions are suitable for treatment using thebeneficial agent formulations (e.g., suspension formulations) andosmotic delivery devices of the present invention, wherein the goal isto provide a treatment comprising two or more beneficial agents. The twoor more beneficial agents may be used to treat the same disease orcondition (e.g., diabetes) or different diseases or conditions (e.g.,obesity and diabetes). In Table 1 a number of disease and conditions arelisted and, provided in the adjacent column to the disease or conditionare proposed beneficial agents for treatment of the disease orcondition. The listed beneficial agents include the listed beneficialagents as well as analogs, variants, and derivatives thereof. Typicallyfor the practice of the present invention, two or more beneficial agentsare selected for administration to a subject in need of treatment,wherein the two or more beneficial agents are formulated as describedherein and administered using the osmotic delivery devices describedherein.

TABLE 1 Disease or A treatment comprising administration of two or moreCondition beneficial agents selected from the following groupObesity/Diabetes Ghrelin antagonists, PYY, Leptin, Obestatin, GLP-1,Exendin, Amylin, G protein coupled receptor GRP 119 agonists, selectiveMelanin Concentrating Hormone (MCH) receptor blockers, Cannabinoid-1agonists, Lipase inhibitors, Neuropeptide Y (NPY) blocker, Oxymodulin,Silent Mating Type Information Regulation 2 homolog-1 (SIRT-1/sirtuin)activators, Oxyntomodulin, Cholecystokinin (CCK) agonists, GastricInhibitory Polypeptide (GIP) agonists Hepatitis interferons; proteaseinhibitors, e.g., Telaprevir (VX-950; Vertex Pharmaceuticals, Inc.);antibodies (e.g., monoclonal, humanized, polyclonal, single-chain)Alzheimer's disease secretase inhibitor, gamma secretase inhibitor,gamma secretase modulators, alpha secretase stimulators, serotonininhibitors Alzheimer's disease Metal protein attenuation compounds, Ionchannel blockers, Oligomeric amyloid beta formation inhibitorsAlzheimer's disease RAGE inhibitors (Receptor for Advance Glycationendproducts), Antibodies targeting amyloid beta Alzheimer's diseaseGSK-3B Kinase inhibitors, Cdk5/p25 Kinase inhibitors, Extracellularsignal-regulated kinase 2 (ERK2) inhibitors, C- abl Kinase inhibitors,MARK Kinase inhibitors, Protein phosphate promoters (PP-2A) Alzheimer'sdisease Modulators of Amyloid beta production (e.g., secretaseinhibitor, gamma secretase inhibitor, gamma secretase modulators, oralpha secretase stimulators), Inhibitors of inhibit amyloid betaaggregation (e.g., Metal protein attenuation compounds, Ion channelblockers, or Oligomeric amyloid beta formation inhibitors), Amyloid betaload reducer (e.g., RAGE inhibitors (Receptor for Advance Glycationendproducts), or Antibodies targeting amyloid beta), Tau- relatedmicrotubule destabilization inhibitors (GSK-3B Kinase inhibitors,Cdk5/p25 Kinase inhibitors, ERK2 Kinase inhibitors, C-abl Kinaseinhibitors, MARK Kinase inhibitors, Protein phosphate promoters (PP-2A))Bone Fractures Receptor activator of NF-.kappa.B ligand (RANKL)activators, Bone Morphogenetic Protein-7 (BMP-7) Bone loss during (RANKLactivator and Bisphosphonates) and (Aromatase cancer treatmentinhibitors for breast cancer OR Anti-androgens for prostate cancer ORluteinizing hormone-releasing hormone (LHRH) agonists for prostatecancer) Rheumatoid Arthritis An anti-CD 20 agent, a JAK3 (janus kinase3) inhibitor, a CCR1 (chemokine [c-c motif] receptor 1) antagonist, aSyk (spleen tyrosine kinase) inhibitor, a P38 MAP kinase inhibitor,CTLA-4 (cytotoxic T-lymphocyte antigen 4), a Tumor necrosis factor(TNF)-alpha antagonist, a TNF-alpha ligand, a steroid, an inhibitor ofthe IL-12 Superfamily of cytokines (IL-1, 6, 12, 15, 17, 18, 32) Cancer(Vascular endothelial growth factor (VEGF) blocker or VEGF receptorligand), (Platelet-derived growth factor (PDGF) blocker or PDGF receptorligand), a receptor tyrosine kinase inhibiting (rtki) compound Cancer (aRAS kinase inhibitor or a RAF kinase inhibitor or a MEK kinase inhibitoror an ERK kinase inhibitor) and (an AKT kinase inhibitor or an inhibitorof the mammalian target of rapamycin (mTOR) kinase or S6k1 or 4E-BP1)Cancer An angiogenesis inhibitor (e.g., VEGF blocker, VEGF receptorligand, PDGF blocker, PDGF receptor ligand, EGF blocker, a receptortyrosine kinase inhibiting (rtki) compound), a tumor cell pathwayinhibitor (e.g., a RAS kinase inhibitor or a RAF kinase inhibitor or aMEK kinase inhibitor, an ERK kinase inhibitor, a RAS kinase inhibitor ora RAF kinase inhibitor or a MEK kinase inhibitor, an ERK kinaseinhibitor), inhibitors of chromatin modification (e.g., an inhibitor ofHistone Deacetylase (HDAC), an inhibitor of histone acetyltransferase(HAT)) Cancer A TNF-alpha antagonist, a TNF-related apoptosis inducingligand (TRAIL) antibody Cancer A Wnt inhibitor, a Hh (hedgehog)inhibitor Cancer A PI-3 Kinase inhibitor, a MEK kinase inhibitor CancerA PI-3 Kinase inhibitor, an mTOR kinase inhibitor Cancer An epidermalgrowth factor receptor tyrosine kinase inhibitor (EGFr-TKI), a B-cellleukemia/lymphoma 2 (BCL-2) blocker Cancer TRAIL receptor antibody, atraditional cytotoxic compound Cancer A P38 MAP kinase inhibitor and (aRaf kinase inhibitor, a MEK kinase inhibitor, or an ERK kinaseinhibitors) Cancer A EGFr TKI, an ERB2 inhibitor

The above-described treatments can be coupled to other treatments aswell, for example, to oral, parenteral injection (e.g., subcutaneous,intramuscular, intraorbital, intracapsular, intraspinal, intrasternal,intravenous, intraperitoneal), bolus, infusion, or other administrationmethods. An example of a co-administered treatment method is the use oftraditional cytotoxics for chemotherapy during cancer treatment with twoor more beneficial agents that are administered using the formulationsand devices described herein. Another example is the co-administrationof acetycholinesterase inhibitors and/or N-methyl-D-aspartic acid (NMDA)receptor antagonists for the treatment of Alzheimer's disease with twoor more beneficial agents that are administered using the formulationand devices described herein.

EXPERIMENTAL

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the devices, methods, and formulae of the presentinvention, and are not intended to limit the scope of what the inventorregards as the invention. Efforts have been made to ensure accuracy withrespect to numbers used (e.g., amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Accordingly,specific values are typical approximate values unless otherwiseindicated. Unless indicated otherwise, parts are parts by weight,molecular weight is weight average molecular weight, temperature is indegrees Centigrade, and pressure is at or near atmospheric.

The compositions produced according to the present invention meet thespecifications for content and purity required of pharmaceuticalproducts.

Example 1 Exendin-4 Particle Formulation

This example describes making an exendin-4 particle formulation.Exendin-4 (0.25 g) was dissolved in 50 mM sodium citrate buffer at pH6.0. The solution was dialyzed with a formulation solution containingsodium citrate buffer, sucrose, and methionine. The formulated solutionwas then spray dried using Buchi 290 with 0.7 mm nozzle, outlettemperature of 75° C., atomization pressure of 100 Psi, solid content of2%, and flow rate of 2.8 mL/min. The dry powder contained 21.5 wt % ofexendin-4 with 4.7% residual moisture and 0.228 g/ml density. The ratioof the components in this particle formulation is as follows:approximately 1.1:1:1:2 (exendin-4:methionine:sucrose:citrate buffer).

This exendin-4 dry powder particle formulation provides an example of abeneficial agent for use in the formulations, devices, and methods ofthe present invention.

Example 2 Oxyntomodulin Particle Formulation

This example describes making an oxyntomodulin particle formulation.Oxyntomodulin (1 g) is dissolved in 50 mM sodium citrate buffer at pH6.0. The solution is dialyzed with a formulation solution containingsodium citrate buffer, sucrose, and methionine. The formulated solutionis then spray dried using Buchi 290 with 0.7 mm nozzle, outlettemperature of 80° C., atomization pressure of 100 Psi, solid content of2%, and flow rate of 2.5 mL/min. The dry powder contains 25% ofOxyntomodulin. The ratio of the components in this particle formulationis as follows: approximately 1.35:1:1:2(Oxyntomodulin:methionine:sucrose:citrate buffer).

This oxyntomodulin dry powder particle formulation provides an exampleof a beneficial agent for use in the formulations, devices, and methodsof the present invention.

Example 3 Particle Formulation of Gut Hormone Fragment PYY

This example describes making a PYY particle formulation, wherein thePYY peptide is the PYY₃₋₃₆ variant. PYY (1 g) is dissolved in 50 mMsodium citrate buffer at pH 6.0. The solution is dialyzed with aformulation solution containing sodium citrate buffer, sucrose, andmethionine. The formulated solution is then spray dried using Buchi 290with 0.7 mm nozzle, outlet temperature of 80° C., atomization pressureof 100 Psi, solid content of 2%, and flow rate of 2.5 mL/min. The drypowder contains 25% of PYY. The ratio of the components in this particleformulation is as follows: approximately 1.35:1:1:2(PYY:methionine:sucrose:citrate buffer).

This PYY dry powder particle formulation provides an example of abeneficial agent for use in the formulations, devices, and methods ofthe present invention.

Example 4 Multiple Beneficial Agent Particle Formulation

This example describes making particle formulations that each comprisemultiple beneficial agents, for example, using exendin-4, oxyntomdulin,and PYY at a predetermined ratios.

A. A Dry Powder Particle Formulation Comprising Exendin-4 andOxyntomodulin.

Exendin-4 (0.5 g) is dissolved in 25 mM sodium citrate buffer at pH 6.0.The solution is dialyzed with a formulation solution containing sodiumcitrate buffer, sucrose, and methionine. Oxyntomodulin (2.5 g) isdissolved in 25 mM sodium citrate buffer at pH 6.0. The solution isdialyzed with a formulation solution containing sodium citrate buffer,sucrose, and methionine. The formulated Exendin-4 solution andOxyntomodulin solution are then mixed together at anExendin-4/Oxyntomodulin ratio of 1:5. The solution is spray dried usingBuchi 290 with 0.7 mm nozzle, outlet temperature of 80° C., atomizationpressure of 100 Psi, solid content of 2%, and flow rate of 2.5 mL/min.The dry powder contains 5% of Exendin-4 and 25% of Oxyntomodulin. Theratio of the components in this particle formulation is as follows:approximately 0.3:1.4:1:1:2(Exendin-4:Oxyntomodulin:methionine:sucrose:citrate buffer).

B. A Dry Powder Particle Formulation Comprising Exendin-4 and PYY.

Exendin-4 (0.5 g) is dissolved in 25 mM sodium citrate buffer at pH 6.0.The solution is dialyzed with a formulation solution containing sodiumcitrate buffer, sucrose, and methionine. PYY (2.5 g), wherein the PYYpeptide is the PYY₃₋₃₆ variant, is dissolved in 25 mM sodium citratebuffer at pH 6.0. The solution is dialyzed with a formulation solutioncontaining sodium citrate buffer, sucrose, and methionine. Theformulated Exendin-4 solution and PYY solution are then mixed togetherat an Exendin-4/PYY ratio of 1:5. The solution is spray dried usingBuchi 290 with 0.7 mm nozzle, outlet temperature of 80° C., atomizationpressure of 100 Psi, solid content of 2%, and flow rate of 2.5 mL/min.The dry powder contains 5% of Exendin-4 and 25% of PYY. The ratio of thecomponents in this particle formulation is as follows: approximately0.3:1.4:1:1:2 (Exendin-4:PYY:methionine:sucrose:citrate buffer).

This example demonstrates the formation of particle formulationscomprising at least two beneficial agents.

Example 5 Interferon Particle Formulation

This example describes making an alpha interferon particle formulation.Alpha interferon (0.5 g) is dissolved in 50 mM sodium citrate buffer atpH 6.0. The solution is dialyzed with a formulation solution containingsodium citrate buffer, sucrose, and methionine. The formulated solutionis then spray dried using Buchi 290 with 0.7 mm nozzle, outlettemperature of 80° C., atomization pressure of 100 Psi, solid content of2%, and flow rate of 2.5 mL/min. The dry powder contains 20% of thealpha interferon. The ratio of the components in this particleformulation is as follows: approximately 1.1:1:1:2(interferon:methionine:sucrose:citrate buffer).

This interferon dry powder particle formulation provides an example of abeneficial agent for use in the formulations, devices, and methods ofthe present invention.

Example 6 Formulations of Amphotericin B

This example describes making two Amphotericin B formulations.

A. Amphotericin B in Single Solvent Vehicle.

Amphotericin B (350 mg) is transferred into a 10 mL volumetric flask.Dimethyl sulfoxide (DMSO) is added to form an Amphotericin B solutionhaving a concentration of 35 mg/mL.

This Amphotericin B solution formulation provides an example of a smallmolecule beneficial agent for use in the formulations, devices, andmethods of the present invention.

B. Amphotericin B in Solvent/Polymer Vehicle.

A vehicle is prepared containing the polymer polyvinylpyrrolidonedissolved in the solvent benzyl benzoate at approximately a 50/50 ratioby weight. The vehicle viscosity is approximately 15,000 poise whenmeasured at 33° C. Amphotericin B is dispersed throughout the vehicle ata concentration of 10% by weight.

This Amphotericin B formulation provides an example of a small moleculebeneficial agent for use in the formulations, devices, and methods ofthe present invention.

Example 7 Multiple Beneficial Agents in Osmotic Delivery Devices

This example describes a number of combinations of multiple beneficialagents, wherein the beneficial agents are delivered from an osmoticdelivery device comprising a single beneficial agent chamber.

A. Single Osmotic Delivery Device with Two Particle Formulations.

A vehicle contains the polymer polyvinylpyrrolidone dissolved in thesolvent benzyl benzoate at approximately a 50/50 ratio by weight. Thevehicle viscosity is approximately 15,000 poise when measured at 33° C.Exendin-4 particle formulation from Example 1 (exendin-4 dry particles)and oxyntomodulin particle formulation from Example 2 (oxyntomodulin dryparticles) are dispersed throughout the vehicle at a concentration of10% particles (1:1 for exendin-4 dry particles and Oxyntomodulin dryparticles) by weight to provide a suspension formulation. The suspensionformulation is then loaded into the beneficial agent chamber of anosmotic delivery device, such as the device illustrated in FIG. 1,chamber 16. The osmotic delivery device is capable of providing deliveryof these two beneficial agents continuously.

B. Single Osmotic Delivery Device with Two Particle Formulations.

A vehicle contains the polymer polyvinylpyrrolidone dissolved in thesolvent benzyl benzoate at approximately a 50/50 ratio by weight. Thevehicle viscosity is approximately 15,000 poise when measured at 33° C.Exendin-4 particle formulation from Example 1 (exendin-4 dry particles)and PYY particle formulation from Example 3 (PYY dry particles) aredispersed throughout the vehicle at a concentration of 10% particles(1:1 for exendin-4 dry particles and PYY dry particles) by weight toprovide a suspension formulation. The suspension formulation is thenloaded into the beneficial agent chamber of an osmotic delivery device,such as the device illustrated in FIG. 1, chamber 16. The osmoticdelivery device is capable of providing delivery of these two beneficialagents continuously.

C. Single Osmotic Delivery Device with One Particle Formulation HavingTwo Beneficial Agents.

A vehicle contains the polymer polyvinylpyrrolidone dissolved in thesolvent benzyl benzoate at approximately a 50/50 ratio by weight. Thevehicle viscosity is approximately 15,000 poise when measured at 33° C.Particles from Example 4A containing 5% exendin-4 and 25% oxyntomodulinare dispersed throughout the vehicle at a concentration of 10% particlesby weight to provide a suspension formulation. The suspensionformulation is then loaded into the beneficial agent chamber of anosmotic delivery device, such as, the device illustrated in FIG. 1,chamber 16. The osmotic delivery device is capable of providing deliveryof these two beneficial agents continuously.

D. Single Osmotic Delivery Device with One Particle Formulation HavingTwo Beneficial Agents.

A vehicle contains the polymer polyvinylpyrrolidone dissolved in thesolvent benzyl benzoate at approximately a 50/50 ratio by weight. Thevehicle viscosity is approximately 15,000 poise when measured at 33° C.Particles from Example 4B containing 5% exendin-4 and 25% PYY aredispersed throughout the vehicle at a concentration of 10% particles byweight to provide a suspension formulation. The suspension formulationis then loaded into the beneficial agent chamber of an osmotic deliverydevice, such as, the device illustrated in FIG. 1, chamber 16. Theosmotic delivery device is capable of providing delivery of these twobeneficial agents continuously.

Example 8 Multiple Beneficial Agents in Osmotic Delivery DevicesComprising Multiple Beneficial Agent Chambers

This example describes a number of combinations of multiple beneficialagents, wherein the beneficial agents are delivered from an osmoticdelivery device comprising more than one beneficial agent chamber.

A. Single Osmotic Delivery Device with Three Beneficial Agent Chambers.

A vehicle containing the polymer polyvinylpyrrolidone is dissolved inthe solvent benzyl benzoate at approximately a 50/50 ratio by weight.The vehicle viscosity is approximately 15,000 poise when measured at 33°C.

Exendin-4 particle formulation from Example 1 (exendin-4 dry particles)is dispersed throughout the vehicle at a concentration of 10% particlesby weight to provide a suspension formulation. The suspensionformulation is then loaded into a first beneficial agent chamber of anosmotic delivery device, such as described in FIG. 3, chamber 330.

Oxyntomodulin particle formulation from Example 2 (oxyntomodulin dryparticles) is dispersed throughout the vehicle at a concentration of 10%particles by weight to provide a suspension formulation. The suspensionformulation is then loaded into a second beneficial agent chamber of anosmotic delivery device, such as described in FIG. 3, chamber 340.

PYY particle formulation from Example 3 (PYY dry particles) is dispersedthroughout the vehicle at a concentration of 10% particles by weight toprovide a suspension formulation. The suspension formulation is thenloaded into a third beneficial agent chamber of an osmotic deliverydevice, such as described in FIG. 3, chamber 350. The osmotic deliverydevice is capable of providing delivery of these three beneficial agentscontinuously.

B. Single Osmotic Delivery Device with Two Beneficial Agent Chambers.

Alpha interferon particle formulation from Example 5 (interferon dryparticles) is dispersed throughout a vehicle at a concentration of 10%particles by weight to provide a suspension formulation. The vehiclecontains the polymer polyvinylpyrrolidone dissolved in the solventbenzyl benzoate at approximately a 50/50 ratio by weight. The vehicleviscosity is approximately 15,000 poise when measured at 33° C. Thesuspension formulation is then loaded into a first beneficial agentchamber of an osmotic delivery device, such as described in FIG. 4,chamber 450.

Amphotericin B solution formulation from Example 6A is then loaded intoa second beneficial agent chamber of an osmotic delivery device, such asdescribed in FIG. 4, chamber 460. The osmotic delivery device is capableof providing delivery of these two beneficial agents continuously.

C. Single Osmotic Delivery Device with Two Beneficial Agent Chambers.

Alpha interferon particle formulation from Example 5 (interferon dryparticles) is dispersed throughout a vehicle at a concentration of 10%particles by weight to provide a suspension formulation. The vehiclecontains the polymer polyvinylpyrrolidone dissolved in the solventbenzyl benzoate at approximately a 50/50 ratio by weight. The vehicleviscosity is approximately 15,000 poise when measured at 33° C. Thevehicle viscosity is approximately 15,000 poise when measured at 33° C.The suspension formulation is then loaded into a first beneficial agentchamber of an osmotic delivery device, such as described in FIG. 4,chamber 450.

Amphotericin B formulation from Example 6B, Amphotericin B inpolyvinylpyrrolidone/benzyl benzoate, is then loaded into a secondbeneficial agent chamber of an osmotic delivery device, such asdescribed in FIG. 4, chamber 460. The osmotic delivery device is capableof providing delivery of these two beneficial agents continuously.

As is apparent to one of skill in the art, various modification andvariations of the above embodiments can be made without departing fromthe spirit and scope of this invention. Such modifications andvariations are within the scope of this invention.

1. An osmotic delivery device comprising: a beneficial agent formulationcomprising: (i) a non-aqueous, viscous vehicle comprising a solvent anda polymer, the vehicle having a viscosity of between about 12,000 toabout 18,000 poise at 33° C.; and (ii) two or more polypeptides, whereina first polypeptide is Glucagon-like peptide-1 (GLP-1) or exenatide anda second polypeptide is selected from the group consisting of amylin, anamylin analogue, a ghrelin antagonist, a G protein coupled receptor 119(GRP 119) agonist, and leptin, wherein the two or more polypeptides aresuspended in the vehicle.
 2. The device of claim 1, wherein the two ormore polypeptides are formulated into one particle formulation that issuspended in the vehicle.
 3. The device of claim 1, wherein the firstpolypeptide is formulated into a first particle formulation and thesecond polypeptide is formulated into a second particle formulation, andthe first and second particle formulations are suspended in the vehicle.4. The device of claim 1, wherein the first polypeptide is exenatide andthe second polypeptide is amylin.
 5. The device of claim 1, wherein thefirst polypeptide is exenatide and the second polypeptide is an amylinanalogue.
 6. The device of claim 5, wherein the amylin analogue ispramlintide.
 7. The device of claim 1, wherein the first polypeptide isexenatide and the second polypeptide is a ghrelin antagonist.
 8. Thedevice of claim 1, wherein the first polypeptide is exenatide and thesecond polypeptide is a GRP 119 agonist.
 9. The device of claim 1,wherein the first polypeptide is exenatide and the second polypeptide isleptin.
 10. The device of claim 1, wherein the first polypeptide isGLP-1 and the second polypeptide is amylin.
 11. The device of claim 1,wherein the first polypeptide is GLP-1 and the second polypeptide is anamylin analogue.
 12. The device of claim 11, wherein the amylin analogueis pramlintide.
 13. The device of claim 1, wherein the first polypeptideis GLP-1 and the second polypeptide is a ghrelin antagonist.
 14. Thedevice of claim 1, wherein the first polypeptide is GLP-1 and the secondpolypeptide is a GRP 119 agonist.
 15. The device of claim 1, wherein thefirst polypeptide is GLP-1 and the second polypeptide is leptin.
 16. Thedevice of claim 1, wherein the beneficial agent formulation comprises athird polypeptide selected from PYY and oxyntomodulin.
 17. The device ofclaim 1, wherein the solvent is selected from the group consisting oflauryl lactate, lauryl alcohol, and benzyl benzoate.
 18. The device ofclaim 1, wherein the polymer is polyvinylpyrrolidone.
 19. The device ofclaim 17, wherein the polymer is polyvinylpyrrolidone.
 20. The device ofclaim 1, wherein the solvent is benzyl benzoate and the polymer ispolyvinylpyrrolidone. 21-63. (canceled)